Basic esters of polyhydro-2-phenanthrylidene-acetic acids

ABSTRACT

Alkyl polyhydro-2-phenanthrylideneacetates are prepared by interacting the corresponding 2-oxopolyhydrophenanthrenes with a tri-lower-alkyl Alpha -phosphono-lower-alkanoate. Said alkyl polyhydro-2-phenanthrylideneacetates are hydrolyzed to the free acid, and then reesterified via the acid chloride with a tertiaryamino-lower-alkanol to give basic esters having cardiotonic activity.

United States Patent 11 1 Shaw et al. Oct. 21, 1975 [54] igff ig fg gfFOREIGN PATENTS OR APPLICATIONS 1,475,540 3 1967 F I 260 468.5 ACETICACIDS l [75] Inventors: Philip E. Shaw, Winter Haven, Fla.; OTHERPUBLICATIONS Sol .l- D m, y; Robert Palma, Helv. Chim. Acta,22:1497-1512 (1939). Clarke Bethlehem both of NY Ruzicka, et al., Helv.Chim. Acta, 23:753-764 1940). Assignee: Sterling Drug -1 New York, NYWadsworth, et al., c. A., 55:18638-18639 (9-61 1. [22] Filed: Nov. 25,1969 Morrison et al., Org. Chem. (A'llyn & Bacon, Boston, [21] pp No;879,921 1959), pp. 474, 484, 500.

Merck lndex, 8th Ed. (Merck. Rahway, NJ., 1968), Related US. ApplicationData pp [63] Continuation-impart of Ser. No. 585,762, Oct. ll,

I966 Primary Examiner-Henry R. .liles Assislanl Examiner-C. M. S. Jaisle[52] US. Cl. 260/327 M; 260/240 1, 260/240.l, Attorney Agent, or FirmThomus L. Johnson; B

260/247.l M; 260/247.l P; 260/247.l S; Woodrow w an 260/247.2 A;260/247.2 B; 260/268 TR; y

260/326.33; 260/326.34; 260/340.7; [57] ABSTRACT I t Cl 260/340'9; figggi'fdg Alkyl polyhydro-2-phenanthrylideneacetates are pre- 5 1 5 295 Bpared by interacting the corresponding 2- 8 82? 1 247*} i loxopolyhydrophenanthrenes with a tri-lower-alkyl 247 1 S 2 A i i Q 3a-phosphono-lower-alkanoate. Said alkyl polyhydro-Z- 326'34 3407 4 9phenanthrylideneacetates are hydrolyzed to the free acid, and thenreesterified via the acid chloride with a References Citedtertlaryammo-lower-alkanol to give basic esters havlng cardiotonicactivity.

10 Claims, N0 Drawings BASIC ESTERS OF POLYHYDRO-Z-PH ENANTHRYLlDENE-ACETIC ACIDS- This application is a continuauon-in-part of ourprior copending application Ser. No. 585,762, filed Oct. ll, 1966, nowUS. Pat. No. 3,592,838.

This invention relates to tricyclic substituted acids and estersthereof, and in particular is concerned withpolyhydro-Z-phenanthrylideneacetic acids and basic esters thereof, andwith intermediates in the preparation thereof.

One aspect of the invention is concerned with compounds of the formula IC-CO-O-R (cum where n is 2 or 3.

Also included are compounds of formula I having a double bond in the8,8a-position or the 8a,9-position; compounds of formula I wherein theexocyclic double bond is saturated; and compounds of formula I havingtwo identical lower-alkyl groups in the 8-position.

The term lower-alkyl used above in defining the groups R, R" and 12 andcertain subgroups under Z stands for alkyl groups having up to about 6carbon atoms, including such groups as methyl, ethyl, propyl, isopropyl,butyl, hexyl, and the like.

When R in formula l stands for an amino-lower-alkyl group, it representsa lower-alkyl group substituted by a basic amino group. The exact natureof the basic amino moiety is not critical, although it is preferred thatit have a molecular weight less than about 200. A particularly preferredtype of amino-lower-alkyl group has the structure Y--N=B wherein Y isloweralkylene of 2-5 carbon atoms and N=B is unsubstituted amino.lower-alkylamino, di-lower-alkylamino, polymethylenimino of -7 ringmembers and loweralkylated derivatives thereof, 4-morpholinyl and loweralkylated derivatives thereof, or l-piperazinyl and lower-alkylatedderivatives thereof. The term loweralkyl as used in defining portions ofthe amino moiety N=B stands for alkyl groups having up to about 6 carbonatoms.

When Z in formula 1 above stands for (acyl-O)CH, or X stands for(HMO-acyl). the acyl groups are carboxylic acyl groups having from I to12 carbon atoms and molecular weights less than about 250.Representative ofthe lower-carboxylic acyl radicals which can be present are lower-alkanoyl, e.g., acetyl. propionyl, isobutyryl, caproyl,heptanoyl, octanoyl, dodecanoyl, trimethylacetyl, and the like;cycloalkyl-lower-alkanoyl wherein cycloalkyl has 5-6 ring members, e.g.,B-cyclopentylpropionyl, B-cyclohexylpropionyl, and the like; benzoyl;phenyl-lower-alkanoyl or -alkenoyl, e.g.. phenylacetyl,,B'phenylpropionyl, cinnamoyl, and the like; phenoxy-lower-alkanoyl.e.g., p-chlorophenoxyacetyl; carbamyl, including unsubstituted carbamyl,N-lower-alkylcarbamyl, N-phenylcarbamyl and N,N-di-lower-alkylcarbamyl;and pyridylcarbonyl, e.g., nicotinoyl and isonicotinoyl. [n acylradicals containing a phenyl group, the benzene ring thereof can beunsubstituted or substituted by any number and kind of substituentsinert under the reaction conditions used, including lower-alkyl, forexample p-tolyl; lower-alkoxy. for example 3,4-dimethoxyphenyl; halogen(including fluorine, chlorine, bromine and iodine), for example2-bromophenyl; and nitro, for example p-nitrophenyl. The lower-alkyl andlower-alkoxy groups preferably have from I to 4 carbon atoms.

The invention is not limited to any particular stereochemicalconfiguration of the compounds of formula I, although a preferredconfiguration of the ring system is trans-anti-trans (4aa,4bB.8aa,l0aB),such compounds being derived from readily available starting materials.

A further aspect of the invention is concerned with compounds of theformula C-CO-O-R wherein:

R is hydrogen, lower-alkyl or amino-lower-alkyl;

R is hydrogen or lower-alkyl; and

R' is hydrogen, lower-alkyl or carboxylic acyl of 1-12 carbon atoms.

The terms lower-alkyl, amino-lower-alkyl and acyl have the meaningsgiven above. The invention is not limited to any particularstereochemical configuration of the compounds of formula [1, although apreferred configuration is 4aa,l0aB, such compounds being derived fromreadily available starting materials.

The compounds of formulas l and ll wherein R is lower-alkyl are preparedfrom compounds of formulas Ill and lV, respectively, including compoundsof formula lll having a double bond in the 8,8a-position, 2 being C=O,and compounds of formula III having two identical lowenalkyl groups inthe 8-position and a double bond in the 8a,9-position, Z being C%);

III

RIIIO by reacting compounds of formulas Ill and IV with atri-lower-alkyl a-phosphono-lower-alkanoate of the formula Rodi lP-CHCOOR in the reaction with a tri-lower-alkylwphosphonolower-alkanoate; however, Z can also be O=C if a double bondis present at the 8.811-POhitlOfl,UI't -ultitliiiicai lower-alkyl groupsare in the 8-position. The compounds of formula I wherein Z is O=C,(acyl-O)CH, H NC(=NH)NHN=C, (O NO)CH, [(loweralkyl) N]CH,(piperidino)CH. (4- hydroxypiperidino)CH, or (pyrrolidino)CH can readilybe prepared from the compounds of formula I wherein Z is (HO)CH or O=Cby conventional means as iliustrated in the examples below.

The reaction of compounds of formulas Ill and [V with a tri-lower-alkyla-phosphono-lowcralkanoate gives a mixture of geometric isomers (cis andtrans) involving the groups about the exocyclic double bond. Although inmany instances it is possible to separate the isomers by physical means,it is not essential to the present invention that the isomers beseparated because there is little difference in the physiologicalproperties of the isomers.

The compounds of formulas l and ll wherein R is hydrogen are prepared byalkaline hydrolysis of the compounds of formulas l and [I wherein R islower-alkyl.

The compounds of formulas l and H wherein R is amino-loweralkyl areprepared by esterification of the compounds of formulas l and [I whereinR is hydrogen by employing the appropriate amino-lower-alkanoi 0ramino-lower-alkyl halide. A preferred method comprises reacting the acidhalide ofa free acid of formulas I or H with atertiary-amino-lower-alkanol, although an alternative procedure involvesreacting an alkali metal salt (e.g., sodium salt) of the acid with anamino-loweralkyl halide (e.g., chloride or bromide). Surprisingly, theacid halide process can be used even in the presence ofa free hydroxygroup [Z=(HO)CH]. It appears that if reaction does occur at the hydroxygroup during acid halide formation, the hydroxy group is regeneratedduring the preparation of the basic ester.

The products of formulas l and II are obtained in the form of racemicmixtures of optically active dand 1- forms. lfdesired, the latter can beseparated by conventional resolution procedures, for example, bytreatment of the compounds where R is hydrogen withdehydroabietylamine.-

The intermediates of formula IV can be prepared as illustrated in thefollowing flow sheet.

Clfi-CH COO-lower-alkyl O CH CH (CHZ)/ CH CH O-lower-alkyl O-lower-alkylContinued --P Pd(C) R"'O VI lVA NaBH NuBH vac) R"O Vll VlllA Na liq. Na,H OH OH mo a m vmc VlllB OH o croa m WHO W8 AZ-carbo-lower-alkoxycyclohcxane-l,4-dione 4- ketal (m 2 or 3) isaralkylated with a m-loweralkoxyphenylethyl bromide, and the resultingproduct V is cyclized with acid to yield 3,4,9,lO-tetrahydro-7-lower-alkoxy-2(lH)-phenanthrone (Vl). Catalytic hydrogenation of V1 withpalladium-on-carbon gives a compound of formula IV having the4aa,l0aaconfiguration (IVA). Sodium borohydride reduction of VI gives1,2,3 ,4 ,9 ,l 0-hexahydro-7 -methoxy-2- phenanthrol (Vll).Sodium-liquid ammonia reduction of the latter provides a mixture ofl,2,3,4,4aa,9,l0,10-

aB-octahydro-7-lower-alkoxy-2B- and Za-phenanthrol (VlllC and WHO),which can be oxidized with chromic oxide to give a compound of formulaIV having the 4aa.l0aB-configuration (lVB). Sodium borohydride reductionof IVA gives a mixture of 1,2,3,4,4aa,9,l0,l-0aa-octahydro-7-lower-alkoxy-2B- and 2a phenanthrol (VlllA and VlllB).

The compounds of formula lll wherein R and R are hydrogen, X is H: and Zis (HO)CH are prepared by reduction of the octahydrophenanthrenes offormulas VlllA-D, as follows:

A compound of formula Vlll is first reduced with lithium and liquidammonia in the presence of alcohol (Birch reduction) followed byhydrolysis to give a 4.4a- ,4b,5,6,7.8,8a9,lO-decahydro-7-hydroxy-2(3H)- phenanthrone (IX), which can then bereduced further either catalytically or by alkali metal-ammoniareduction to give 3,4,4a,4b,5,6,7.8.8a.9,10.10adodecahydro-7-hydroxy-2(l H )-phenanthrone (X) (III; 2 is (HO)CH, R and R" H, X H,). Thestereochemistry of the ring system and the 7-hydroxy group is dependentupon the particular Vlll isomer used and the nature of the reduction ofIX. as will be apparent from the specific examples below. The functiongroups of X can also be altered by conventional means as will beillustrated by the examples below.

The compounds of formula I" wherein R is methyl can be prepared from thecompound:

Reduction of the double bond of XI affords a compound of formula "Iwherein Z is (HO)CH, R' is CH R" is H and X is H The compounds offormula [11 wherein R is loweralkyl are prepared from compounds of theformula n (R' c11 Reduct ion by reductive alkylation with lithium inliquid ammonia and a lower-alkyl halide.

The compounds of formula [II wherein R is OH or X is O can be preparedby microbiological oxidation of compound lX above. When [X is incubatedwith a culture medium of an organism of the genus Cunninghamella thereis obtained a mixture of the hydroxylated products:

and

XII

XIII

Treatment of XII with sulfuric acid in acetic acid converts it byrearrangement to a compound of formula [II where Z is (CH COO)CH, R isH, R" is H and X is =0. Oxidation of X"! with chromic oxide converts itto a compound of formula [II wherein Z is O=C, R is OH, R" is H, X is Hand there is a double bond in the 8.8aposition.

The compounds of formula I" wherein there are two lower-alkyl groups inthe 8-position and a double bond in the 8a,9-position, Z being O=C, areprepared as follows:

lower-allql iower-allqrl XIV lower-allql lower-alkyl XVI Alkylation ofXIV (R is hydrogen or lower-alkyl) with a lower-alkyl halide in thepresence of potassium tertiary-butoxide gives a hydroxy ketone offormula XV. The latter can be oxidized with chromic oxide to thediketone XVI. The lO-oxo group can then be introduced by the action oftertiary-butyl chromate to give the triketone XVII (III; R is H orlower-alkyl, R" is H, X is 0, Z is O=C, 8,8-di-lower-alkyl, AAlternatively, the compounds XV or XVI can be oxidized withtertiary-butyl peracetate in the presence of cuprous chloride tointroduce an acyloxy group into the IQ- position. Hydrolysis andoxidation of the latter then gives the triketone XVII.

Further starting materials for the preparation of compounds of formula Ihaving two identical lower-alkyl groups are of the formula loIer-alkyl"lower-allqrl XVIII where R is hydrogen or lower-alkyl. The compounds offormula XVIII can be prepared from compounds of formula XVI by formingthe mono-ethylene glycol ketal of the 2-oxo group, reducing the 8-oxogroup with lithium aluminum hydride to an 8B-hydroxy group, re-

lower-allcyl iowemallql XVII ducing the 8a,9-double bond with hydrogenin the presence of palladium-on-carbon, and finally cleaving the 2-ketalgroup. i

The compounds of formula I where the exocyclic double bond is saturatedcan be prepared by hydrogenation (palladium-on-carbon) of theunsaturated analogs where R is loweralkyl.

The structures of the compounds of the invention were established by themodes of synthesis, by elementary analysis, by interpretation of theirinfrared, ultraviolet and NMR spectra, and by their behavior in thinlayer chromatography (TLC) and gas-liquid phase chromatography (glpc).

The compounds of formulas I and II wherein R is amino-lower-alkyl arebasic in nature and form acidaddition salts with moderate to stronginorganic or organic acids. For pharmacological purposes it is preferredto use water-soluble, pharmaceutically acceptable acid-addition salts,although all acid-addition salts are useful as characterizingderivatives of and as intermediates in the purification of the freebases.

Pharmacological evaluation of the basic ester compounds of the inventionhas shown that they possess cardiotonic activity similar to that shownby the alkaloid cassaine and are thus useful in increasing theventricular contractile force of the mammalian heart. The compounds areprepared for use in the form of a sterile aqueous solution of awater-soluble, pharmaceutically acceptable acid-addition salt. Theamidinohydrazone derivatives of the intermediate tricyclic ketones alsohave similar cardiotonic activity.

Chemotherapeutic evaluation has shown that the compounds of formula Iwherein R is hydrogen possess bacteriostatic activity.

The following examples will further illustrate the invention without thelatter being limited thereby.

EXAMPLE 1 2-Carbomethoxy-2-(mmethoxyphenethyl)- cyclohexane-l,4-dione4-ethylene ketal [V; R is 3] A solution of 5.33 g. (0.047 mole) ofpotassium tbutoxide in 100 ml. of t-butanol was stirred while 10.0 g.(0.047 mole) of 2-carbomethoxycyclohexane-l,4- dione 4-ethylene ketal in150 ml. of t-butanol was added. An additional 100 ml. of t-butanol wasadded, followed by 10 g. (0.047 mole) of m-methoxyphenethyl bromide. Thesuspension was refluxed and stirred mechanically for 72 hours. At thispoint the reaction mixture was slightly alkaline to pH paper. Thereaction mixture was cooled and added to ice water. Ether was addedfollowed by dilute hydrochloric acid. The layers were separated. and theether layer was washed with a saturated sodium bicarbonate solution. Theether was extracted twice with 200-ml. portions of 5% aqueous potassiumhydroxide. The aqueous alkaline solution on acidification withhydrochloric acid yielded 1.45 g. of starting2-carbomethoxycyclohexane-l,4-dione 4- ethylene ketal which wasidentified by its melting point. The ether solution from which thestarting material had been removed was then washed with ice cold dilutehydrochloric acid. saturated sodium bicarbonate solution and saturatedsodium chloride. After drying the ether solution (Na SO the solvent wasremoved to leave a yellow viscous oil. This residue was distilled andthe fraction that boiled at l90205C. (0.08-0.15 mm.) was collected togive 10.1 g. of2-carbomethoxy-2-(mmethoxyphenethyl)-cyclohexane-l,4-dione 4-ethyleneketal. A redistilled sample boiled at 195l96C. (0.180.20 mm.); n 1.5267.

EXAMPLE 2 3,4,9,10-Tetrahydro-7-methoxy-2(1H)-phenanthrone [Vl; R' is CHSulfuric acid (1 liter llN) was added all at once to a solutioncontaining 115.4 g. (0.33 mole) of 2-carbomethoxy-2-(m-methoxyphenethyl)-cyclohexane- 1,4-dione 4-ethyleneketal (Example 1) in 1 liter of dioxane. The reaction mixture wasstirred at 100C. in a nitrogen atmosphere for 4% hours. The cooledsolution was poured into ice and enough water was added to bring thetotal volume to 3 liters. The aqueous mixture was extracted with etherseveral times. The combined ether layers were washed with 10% sodiumcarbonate and finally with saturated sodium chloride solution. The ethersolution was dried (Na SO and evaporated by warming in vacuo to afford73.9 g. ofa red oil. This material was chromatographed on 2 kg. ofsilica gel. Elution with 4 liters of etherpentane (1:9) and liters ofether-pentane (1:3) removed less polar material. Continued elution with5.5 liters of ether-pentane (1:3) afforded 18.2 g. of an oil whichcrystallized from ether containing hexane to give 16.5 g. of 3,4,9.l0-tetrahydro-7-methoxy2( 1 H )-phenanthrone. m.p. 7577C. Further elution(5 liters) gave an additional 17.8 g. of the compound.

EXAMPLE 3 1,2,3,4,9.l0-Hexahydro-7-methoxy-2-phenanthrol [V1l; R is CH Asolution of 36.7 g. (0.16 mole) of 3,4,9.l0- tetrahydro-7-methoxy-2( l H)-phenanthro:- l nrnplc 2) in 1500 ml. of ethanol was treated with 19 g.of sodium borohydride in 150 ml. of water. After 3 hours at roomtemperature. acetone was added to the reaction mixture to decompose theexcess borohydride. The volume was reduced to about 400 ml. by warmingin vacuo. Water and ether were added and the layers were separated. Theether was washed with saturated sodium chloride solution. The aqueouslayers were washed again with fresh ether and the organic layers werethen combined. The ether solution was dried (Na SO.,) and the solventwas removed leaving behind an oily residue (36.1 g.). Crystallizationfrom ether containing hexane gave 20.3 g. of 1,2,3,4,9.10-hexahydro-7-methoxy-2-phenanthrol. m.p. 9394C. Further concentration of the motherliquor afforded another 9.3 g. of the compound, m.p. 9092C.

EXAMPLE 4 3,4,4aa,9,l0,10aa-Hexahydro-7-methoxy-2(1H) phenanthrone [1VA;R' is CH;,]

A solution of 1 g. (4.4 mmoles) .of 3,49,10- tetrahydro-7-methoxy-2-( 1H)-phenanthrone (Example 2) in 300 m1. of ethyl acetate was hydrogenatedat a pressure of 3.86 kg./c:m and room temperature in the presence ofmg. of 10% palladium-on-carbon. After 1 hour the hydrogenation wascomplete and the catalyst was removed by filtration. The solvent wasremoved by warming in vacuo and the residue was crystallized from ethercontaining hexane to yield 900 mg. 3 ,4,4aa,9, 10,10aa-hexahydro-7-methoxy-2( 1H phenanthrone, m.p. 92-93C. and a secondcrop (100 mg.), m.p. 899lC.

EXAMPLE 5 1.2,3,4,4aa,9,10,lOaa-Octahydro-7-methoxy-2B- phenanthrol and-2a-phenanthrol [VlllA and B; R' is 3] (Method 1) A solution of 15 g.(0.066 mole) of 1,2,3,4,9,l0- hexahydro-7-methoxy-2-phenanthrol (Example3) in 300 ml. of ethyl acetate was hydrogenated at a pressure of 3.86kg./cm and room temperature in the presence of 1.5 g. of 10%palladium-on-carbon. After 45 minutes the hydrogenation was complete andthe catalyst was removed by filtration. The filtrate was combined withthe filtrate of an identical experiment. The solvent was removed bywarming in vacuo to leave 31.5 g. of an oily residue which crystallizedfrom ether containing hexane. Recrystallization of this material fromether con taining hexane afforded 13.6 g. of solid, m.p. 8083C.

The mother liquor was chromatographed on 1.5 kg. of silica gel. Elutionwith 13 liters of ether-pentane 1:1) removed some less polar material.Continued elution with 5.5 liters of solvent of the same concentrationafforded 6 g. of material which, on crystallization from ethercontaining hexane. yielded 4.83 g. of solid, m.p. 8487C. and 0.4 g. ofsolid, m.p. 81-85C. Combination with the original solid obtained bydirect crystallization and recrystallization from ether containinghexane afforded 16.1 g. ofl,2,3,4,4aa,9,10,10aaoctahydro-7-methoxy-2B-phenanthrol (VIIIA), m.p.

8488C. This compound apparently shows polymorphism. Recrystallizationfrom ether containing hexane gave material melting at 77-82C.

Further elution in the above described chromatography, with 2.5 litersof ether-pentane (1:1) gave 4.2 g. of a mixture of two compounds.Finally, elution with another 4 liters of the same solvent mixture gavean oily residue which crystallized from ether containing hexane andafforded 5.3 g. of1,2,3,4,4aa,9,10,-10aaoctahydro-7-methoxy-2a-phenanthrol (VlllB), m.p.67-70C. Recrystallization from ether containing hexane gave 5 g., m.p.89-90.5C.

(Method 2) A solution of 580 mg. (2.5 mmoles) of 3,4,4aa,9,10,-laa-hexahydro-7-methoxy-2( 1H )-phenanthrone (Example 4) in 25 ml. ofabsolute ethanol was treated with 240 mg. of sodium borohydride in 2.5ml. of water. The reaction mixture was kept at room temperatureovernight and the excess borohydride was decomposed by adding acetonefollowed by water. The reaction mixture was washed with ether and theether was washed with saturated sodium chloride solution. The ether wasdried (Na,SO and evaporated to leave 500 mg. of oily residue.

The oily residue was chromatographed on silica gelcoated plates whichwere developed with etherpentane (3:1). About 170 mg. of residue was puton each of 3 plates (20 cm X 40 cm) carrying a l-mm. coating of silicagel. The major band from the plates (less polar) afforded 310 mg. (54%)of 1,2,3,4,4aq,9, l

EXAMPLE 6 1,2,3 ,4,4aa,9,10,lOaB-Octahydro-7 methoxy-2B- phenanthrol and-2a-phenanthrol [VlllC and D; R' is CH;,]

Sodium (3.15 g., 0.137 mole) was dissolved in 1 liter of liquid ammonia.A solution of 15 g. (0.066 mole) of 1,2,3,4,9,10-hexahydro-7-methoxy-2-phenanthrol (Example 3) in 100 ml. oftetrahydrofuran and 25 ml. of aniline was added over a twenty minuteperiod to the ammonia solution which was being stirred. At the end ofthe addition 14 g. (0.26 mole) of ammonium chloride was addedportion-wise during minutes to discharge the blue color. The ammonia wasevaporated and water and ether were added to the residue. The aqueouslayer was separated and extracted twice with ether. The combined etherlayers were washed three times with water, twice with 3N hydrochloricacid, three times with saturated sodium chloride solution, dried (Na,SOand the solvent was removed to leave an amber colored residue. Aftercrystallization and several recrystallizations from ether containinghexane, 4.7 g. of 1,2,3,4,4aa,9,l0,10aB-octahydro-7-methoxy-Za-phenanthrol (VlIlC), m.p. 9899C. was obtained.

The combined mother liquors were chromatographed on 5 kg. of silica gel.Preliminary elution with ether-pentane (1:1) separated some less polaroils which were discarded. Continued elution with etherpentane (1.1:1)afforded first 15 g. of crude 1,2,3,4,4a-01,9,10,1OaB-octahydro-7-methoxy-2B-phenanthrol. Continued elution withthe same solvent system next afforded 12 g. of crudel,2.3,4,4a0z,9,l0,10aaoctahydroJ-methoxy-2B-phenanthrol (VIllA). Furtherelution with ether-pentane (1.5:1) finally gave 53 g. ofan oil whichyielded 13 g. more of l,2,3,4,4aa,9 1-0,l0aB-octahydro-7-methoxy-Za-phenanthrol (VlllD), m.p. 98100C.

Recrystallization of the crude 1,2,3,4,4aa,9, l 0,10al3-octahydro-7-methoxy-2B-phenanthrol from ether afforded 13.75 g. of thisproduct.

A similar chromatographic separation afforded 1,2,-3,4,9,l0-hexahydro-7-hydroxy-2-phenanthrol [Vll; R' is H], m.p.196.5-198C. (10%) when 100% ether was put through the column.

EXAMPLE 7 3 ,4,4aa,9,10,10aB-Hexahydro-7-methoxy-2(1H)- phenanthrone[1VB; R' is CH A solution of 25 g. (0.11 mole) of 1,2,3,4,4aa,9,10,-10aB-octahydro-7-methoxy-2a-phenanthrol in 500 ml. of pyridine was addedto a suspension of 25 g. of chr0- mium trioxide (0.25 mole) in 500 ml.of pyridine. After standing at room temperature for 68 hours, thereaction mixture was added to 1.5 liters of ethyl acetate. The chromiumsalts were removed by passing the suspension through infusorial earth.The solvent was removed by heating in vacuo. Ether was added to theviscous residue and the mixture was filtered again. Evaporation of theether afforded 20 g. of viscous oil. Crystallization from cyclohexanecontaining ether afforded 6 g. of3,4.4aa,9,10.10aB-hexahydro-7-methoxy-2( 1H)- phenanthrone, m.p. 6263C.Concentration of the mother liquor afforded another 4 g., m.p. 5 9 62C.Chromatography of the mother liquors on silica gel and elution withetherpentane (1:3) afforded an additional 6.14 g. of 3,4,4aa,9,l0,lOaB-hexahydro-Imethoxy- 2(11-1)-phenanthrone, m.p. 64.5-66C. whenrecrystallized from ether-hexane.

EXAMPLE 8 A solution of 11 g. (0.05 mole) of 1,2,3,4,4aa,9,10-10aa-octahydro-7-methoxy-2B-phenanthrol (VlllA, Example 5) in 200 ml. oftetrahydrofuran and 200 ml. of t-butyl alcohol was added to 400 ml. ofammonia. Lithium (5.5 g., 0.79 mole) was added to the stirred solutionover a 2 hour period. The reaction mixture, which never became blue butdeveloped a bronzecolored layer, was stirred for an additional 4 hours.Methanol (60 ml.) was added and the ammonia was evaporated. Water andether were added, the mixture shaken and the layers separated. The etherlayer was washed twice with saturated sodium chloride solution. Theaqueous layers were washed with a fresh portion of ether and the etherlayers were combined, dried (Na SO4) and concentrated by warming invacuo. The syrupy residue was dissolved in ml. of dioxane. The dioxanesolution was treated with 75 ml. of 2N hydrochloric acid and heated in anitrogen atmosphere on a steam bath for 30 minutes. Saturated sodiumchloride solution and ether were added to the cooled reaction mixture,the mixture shaken and the layers separated. The ether was washed againwith saturated sodium chloride solution. The aqueous layers were washedagain with a fresh portion of ether. The combined ether layers weredried (Na SO and evaporated by warming in vacuo to leave 11 g. of anoily residue. Crystallization from acetone afforded 5.36 g. of4.4aa,4b,8.5,6.7,- 8,8a/3.9.10-decahydro-7a-hydroxy-2(3H)- phenanthrone, m.p.148151C.. and a crop of 0.4 g., m.p. 144-147C. Recrystallization fromacetone provided a sample with m.p. 150l52C.

EXAMPLE 9 4,4aa,4b[3.5.6.7,8.8aa.9. l-Decahydro-7B-hydroxy-2(3H)-phenanthrone [IX; 7B,4aa,4bfl.8aaconfigurational] A solution of18.33 g. (0.08 mole) of 1,2,3.4,4aa,9,-l0,10aB-octahydro-7-methoxy-2a-phenanthrol (VlllB, Example 5) in 186 ml.of tetrahydrofuran was added to 300 ml. of ammonia. Lithium wire (5.5g., 0.8 mole) was added in 30 minutes with stirring. After an additional 25 minutes a mixture of 60 ml. of absolute ethanol and 60 ml. ofether (anhydrous) was added to discharge the blue color. The solutionwas evaporated to half the volume. Ether and water were added, themixture shaken and the layers separated. The ether was washed withsaturated sodium chloride solution and the aqueous layers were washedwith a fresh portion of ether. The combined ether layers were dried (NaSO and the ether was removed by warming in vacuo. The remaining residuewas taken up in 300 ml. of dioxane and 150ml. of 2N hydrochloric acid.The solution was heated in a nitrogen atmosphere for 30 minutes on asteam bath. Saturated sodium chloride solution and ether were added tothe cooled reaction mixture and the layers were separated. The ether waswashed twice with saturated sodium chloride solution. The aqueous layerswere washed with a fresh portion of ether. The combined ether was dried(Na- $0 and the solvent was removed while warming in vacuo, leaving 18g. of an oily residue that crystallized from ether. Severalrecrystallizations from ether afforded 9.82 g. of 4,4aa,4b-B,5,6,7.8,8aa,9,lO-decahydro-7B-hydroxy-2(3H)- phenanthrone, m.p.l4ll43C., when recrystallized from acetone.

EXAMPLE [0 l ,2,3,4,4aa.9, 10,1 OaB-Octahydro-7-methoxy-2B- phenanthrol(VlllC. Example 6) (5.5 g., 0.024 mole), by the procedure of Example 9,afforded 2.8 g. of4,4aa,4b,B,5.6,7,8,8aa,9,10-decahydro-7a-hydroxy-2(3H)- phenanthrone,m.p. 126.5-128.5C., and a second crop of 0.6 g.. m.p. l23.S-127C. (yield64%), when recrystallized from acetone.

EXAMPLE 11 a. l 0z.4bB,5,6,7,8,8aa,9,10,10am-Tetradecahydrophenanthrene-2B,7B-dio1 7-acetate A solution of 6.95 g.(0.031 mole) of 4,4aa,4b/3,5,6,-7,8,8afi,9,10-decahydro-7a-hydroxy-2(3H)- phenanthrone (Example 8) in250 ml. of tetrahydrofuran and 250 ml. of ether was treated with ml. ofdihydropyran and 200 mg. of p-toluenesulfonic acid, and the solution wasleft at room temperature overnight. Solid sodium carbonate was added toneutralize the acid and the solution was passed through a filter.Pyridine (2 ml.) was added and the volume of the solution was reduced toabout 30 ml. by heating the mixture in vacuo. Tetrahydrofuran (30 ml.)and absolute ethanol (60 ml.) were added to the residue and theresulting solution was added to 500 ml. of liquid ammonia. A total of 7g. (1 mole) of lithium wire was added to the stirred ammoniacal solutionover a 45 minute period. The solution remained blue for about one hourafter addition of the lithium and 30 ml. more of absolute ethanol wasadded to discharge the color. The volume was reduced to one-third. Etherwas added and the solution was heated under reflux conditions to removemore of the ammonia. Water was carefully added, followed by more ether.The layers were separated and the ether was washed with saturated sodiumchloride solution. The aqueous layers were washed with a fresh portionof ether and the combined ether layers were dried (Na SO The solvent wasremoved in vacuo to afford 1,2,3,4,4aa,4bfi,5,6,7,8,8aa,9,10,10aatetradecahydrophenanthrene-2B,7B-diol2- dihydropyranyl ether. Pyridine (30 ml.) and acetic anhydride (15 ml.)were added to the residue. The next morning the excess reagents wereremoved by warming in vacuo. The residue was dissolved in ml. of methanol and 150 ml. of 2N hydrochloric acid. At the end of 45 minutes,ether was added and the layers were separated. The ether was washedtwice with saturated sodium chloride solution. The aqueous layers werewashed with a fresh portion of ether and the combined ether layers weredried (Na,SO The solvent was removed by warming in vacuo and the residuewas chromatographed on 250 g. of silica gel. The fractions eluted withmethylene dichloride-ether-pentane (1:2:2), afforded 2.63 g. ofl,2,3,4,4aa,4bB,5,6,7,8,8a- 01,9, 1 0,- 1Oaa-tetradecahydrophenanthrene-ZBJB-diol 7-acetate, m.p. 166.5167C. whenrecrystallized from ether.

b. 1,2,3,4,4aa,4bB,5,6,7,8,8aa,9,10,10aa-Tetradecahydrophenanthrene-23,7B-diol EXAMPLE 12 3,4,4aa,4bl3,5,6,7,8,8aa,9, 10,10aa-Dodecahydro-7B- hydroxy-2( lH)-phenanthrone [X;7,8,4aa,4bfi,8aa,10aa-configuration] A pyridine solution (30 m1.) of1,2,3,4,4aa,4bB,5,6,- 7,-8,8aa,9,lO,10aa-tetradecahydrophenanthrene-2B,7B-dio1 7-acetate (Example 1 1a) (2.4 g., 0.01 mole) was added to 30ml. of pyridine containing 2.4 g. of chromium trioxide. After standingfor 24 hours at room 'temperature the reaction mixture was added to 500m1.

of ethyl acetate and then filtered. The solvent was removed in vacuo and150 ml. of ether was added to the residue. More salts were filtered awayand the ether was evaporated. The residue containing 3,4,4a'a,4bB.5-,6,7,8,8aa,9,l0,10aa-dodecahydro-7B-hydroxy- 2( lH)-phenanthrone7-acetatc was dissolved in 80 ml. of 5% methanolic potassium hydroxidecontaining 5% water and the solution was boiled under refluxed for 45minutes. Part of the methanol was removed by warming in vacuo. Ether andsaturated sodium chloride were added. The mixture was shaken, the layerswere separated and the ether was washed with saturated sodium chloridesolution. The aqueous layers were washed again with a fresh portion ofether and the combined ether layers were dried (Na SO and evaporated.Crystallization of the residue from ether afforded 1.64 g. of3,4,4aa,4bfi,5,6,7,8,8aa,9,l0,10aa-dodecahydro-7B-hydroxy-2(lH)-phenanthrone, m.p. ll61l7.5C. when recrystallized fromether.

EXAMPLE l3 A solution of 10.75 g. (0.049 mole) of 4,4aa,4bB,5,-6,-7,8,8aa,9,10-decahydro-7B-hydroxy-2(3H)- phenanthrone (Example 9) in225 ml. of tetrahydrofuran and l 10 ml. of ether was added in a steadystream to a stirred solution of liquid ammonia (1.1 liter) containing1.37 g. (0.19 mole) of lithium wire. The dropping funnel used for theaddition was rinsed with another 55 ml. of tetrahydrofuran. Ammoniumchloride (10 g., 0.19 mole) wasadded as quickly as possible withcontrolled boiling. The solvent was evaporated to half the volume. Water(300 ml.) and ether (300 ml.) were added. The ether was boiled underreflux to remove more of the ammonia. More ether and water were addedand the layers were separated. The ether layer was washed with saturatedsodium chloride and was then dried (Na SO Evaporation of the ether leftan oily residue of 11.6 g. The residue was chromatographed on 300 g. ofsilica gel. Elution with methylene dichloride-ether-pentane (2:5:3)afforded 7.9 g. of 3,4- ,4aa,4bB,5,6,7,8,8aa,9,10,10aB-dodecahydro-7B-hydroxy-2(1H)-phenanthrone, m.p. l07108C. when recrystallized fromacetone.

Further elution of the column with ether-methanol (19: 1) afforded 0.9g. of l,2,3,4,4aa,4bfi,5,6,7,8,8aa,- 9, l 0, lOaB-tetradecahydrophenanthrene-ZaJB-diol, m.p. 216218C. whenrecrystallized from ether.

EXAMPLE 14 3 ,4,4aa,4bB,5 ,6,7,8 ,8aa,9,10, lOaB-Dodecahydro-7ahydroxy-2( l H )-phenanthrone [X;7a,4aa,4bB,8aa,1OaB-configuration] Using the reduction proceduredescribed in Example 13,4,4aa,4bB,5,6,7,8,8aa,9,10-decahydro-7ahydroxy-2(3H)-phenanthrone(Example 10) (3.2 g., 0.014 mole) afforded 1.49 g. of3,4,4aa,4bfi,5,6,7,8,8- aa,9,l0,10aB-dodecahydro-7a-hydroxy-2(1H)-phenanthrone, m.p. 137.5138C. when recrystallized from ether.

3,4,4aa,4bfi,5,6,7,8,8aa,9,10,10afl-Dodecahydro- 7a-hydroxy-2(lH)-phenanthrone can be caused to react with methylmagnesium bromide togive 1,2,3,4,4- aa.4bB,5,6,7,8,8aa,9,10,IOaB-tetradecahydro-Z-methyl-2,7a-dihydroxyphenanthrene, and the latter oxidized with chromicoxide to give 3,4,4aa,4bB,5,6,7.8,- 8aa,9, 10,1OaB-dodecahydro-7-methyl-7-hydroxy- 2(lH)-phenanthrone [111; R and R"are H. X is H Z is (HO) (CH )C]3,4,4aa,4b,3,5.6,7,8.8aa,9,10.10aB-Dodecahydro- 7a-hydroxy-2( 1H)-phenanthrone can be ketalized with ethylene glycol and the resultingketal caused to react with sodium to give the sodio derivative of the7ahydroxy group which in turn can be caused to react with methyl iodideto give the 7-methoxy compound. Hydrolysis of the ketal then gives3,4.4aa.4b/3.5,6,7,8.- 8aa,9,10,10aB-dodecahydro-7a-methoxy-2(1H)-phenanthrone [111; R and R" are H, X is H Z is (a-CH O)CH]3.4,4aa,4bB,5,6,'7.8,8aa,9,10.10aB-Dodecahydro- 7a-hydroxy-2(lH)-phenanthrone can be caused to react with p-toluenesulfonyl chloridein pyridine to give the 7a-p-toluenesulfonate, and the latter treatedwith anhydrous potassium fluoride in diethylene glycol, eighteen hoursat l 10C., to give 3,4,4aa,4bfi.5,6,7.8.-8aa,9,10,10aB'dodecahydro-7B-fluoro- 2(1H)phenanthrone [111; R and R"are H, X is H Z is (B-F)CH]. By analogous procedures the correspond ing7B-chloro and 7B-bromo compounds can be prepared.

EXAMPLE 15 3,4,4aa,4bB,5,6,7,8,8a/3,9,10,10aB-Dodecahydr0-7ahydroxy-2(1H)-phenanthrone IX;7a,4aa,4bB,8aB, 1 oafl'configurationl Using the lithium-ammoniaprocedure of Example 13 for reduction.4,4aa,4bB,5,6,7,8,8aB,9,l0-decahydro- 7a-hydroxy-2(3H)-phenanthrone(Example 8) (5.5 g., 0.0 25 mole) afforded 2.7 g. of3,4,4aa,4bB,5,6,7,8,8a- B;9;l.0,10aB-dodecahydro-7a-hydroxy-2( 1H"ph'enanthrone, m.p. 82-83C. when recrystallized from ether containinghexane.

EXAMPLE l6 3,4,4aa,4b[3,5 ,6,7,8,8aa,9,10,10aB-Dodecahydro-7B-hydroxy-2( 1H)-phenanthrone amidinohydrazone A solution of3.5 g. (0.016mole) of 3,4,4aa,4bB,5,6-,-7,8,8aa,9,10.10aB-dodecahydro-7B-hydroxy-2(1H)- phenanthrone (Example13) in 50 ml. of methanol was added to l 15 ml. of methanol containing4.93 g. (0.036 mole) of aminoguanidine bicarbonate and 12 ml. ofconcentrated hydrochloric acid. After standing at room temperatureovernight, the reaction mixture was added to 1 liter of ether. Aprecipitate formed which was found to be crude aminoguanidinehydrochloride and was removed by filtration. Dilution of the filtratewith more ether then precipitated the desired product (3.28 g., 66%).Recrystallization was effected by adding ether to a methanolic solutionof the solid, to give 3,4,-4aa,4bfi,5,6,7,8,8aa,9,10,10aB-dedecahydro-7B-hydroxy-2(lH)-phenanthrone amidinohydrazone in the form of itshydrochloride salt, m.p. 245253C. (evacuated tube).

EXAMPLE l7 3 ,4,4aa,4bB,5 ,6,7,8,8aa.9,10,10aB-Dodecahydro-7B-hydroxy-2( l1-1)-phenanthrone 2,2-ethylene dithioketal A soolution of4 g. (0.018 mole) of hydroxy ketone3,4,4aa,4bB,5,6,7,8,8aa,9,10,10aB-dodecahydro-7B-hydroxy-2(lH)-phenanthrone (Example 13) in 50 ml.

of glacial acetic acid was treated with ml. of ethane dithiol. Themixture was warmed slightly to effect solution and 4 ml. of borontrifluoride etherate was added to the warm solution. After the mixturehad stood at room temperature for 5 minutes, water was added and theprecipitated solid was collected. The solid (4.5 g.) was dissolved in100 ml. of 5% methanolic potassium hydroxide containing 5% water and themixture was boiled under reflux for 30 minutes. The volume of methanolwas reduced by warming in vacuo and ice water was added. The precipitatewas recrystallized from acetone and afforded 2.94 g. of3,4,4aa,4bB,5.6,- 7,8,8acz,9,10,lOaB-dodecahydro-7/3-hydroxy-2(1H)-phenanthrone 2,2-ethylene dithioketal, m.p. 129-130C.

EXAMPLE 18 3,4,4aa,4bB,5 .6,7,9,10,10aB-Decahydro-7-oxo-2(1H)phenanthrone [111; R and R" are H, X is H Z is O=C, A

A solution of 5.14 g. (0.023 mole) of 4,4aa,4bfi,5,6,-7,8,8aa,9,10-decahydro-7B-hydroxy-2(3H)- phenanthrone (Example 9) in 50ml. of pyridine was added to 50 ml. of pyridine containing 5.15 g. ofchromium trioxide. After being stirred overnight the reaction mixturewas added to 500 ml. of ethyl acetate. The mixture was filtered and thesolvent was removed by warming in vacuo. Ether (150 ml.) was added andmore solid was filtered off. The solvent was evaporated leaving 4.69 g.of an oily residue that crystallized. Recrystallization from etherafforded 3.27 g. (63%) of 3,-4,4aa.4bB.5,6,7,9,l0.10aB-decahydro-7-oxo-2(1H)- phenanthrone, m.p.l24125C.

EXAMPLE 19 l.2,3,4,4aa,4bB,5,6,7,8,8aa,9,10,10aB-Tetradecahydrophenanthrene-2,7-dione A solution of 3.2 g. (0.014 mole)of l,2,3,4,4aa,4b- B,-5,6,7,8.8aa,9,10,10aB-tetradecahydrophenanthrene-2a,7B-diol (Example 11b) in 60ml. of pyridine was added to 60 ml. of pyridine containing 6.4 g. ofchromium trioxide. After being stirred overnight the reaction mixturewas added to 600 ml. of ethyl acetate. The mixture was filtered and thesolvent was removed by warming in vacuo. Ether (150 ml.) was added andmore solid was removed by filtration. Upon concentration of the ether,there was obtained 1.51 g. of 1.2,3,4,-4aa,4bB,5,6,7,8,-8aa,9,10,10aB-tetradecahydrophenanthrene-2,7-dione,m.p. l52.5154C. Upon further concentration, another 0.7 g., m.p.l49.5l5l.5C. was obtained.

EXAMPLE 20 bl3,5,6,7,8,8aa,9, l O, l OaB-Tetradecahydrophenanthrene-2.7-dione bisamidinohydrazone A solution of4.83 g. (0.022 mole) of 1,2,3,4,4aa,4b-B-5.6,7,8.8aa,9,10,10aB-tetradecahydrophenanthrene-2,7-dione in 75 ml.of methanol was added to a solution of 13.6 g. (0.100 mole) ofaminoguanidine bicarbonate and 35 ml. of concentrated hydrochloric acidin 315 ml. of methanol. After 24 hours at room temperature, the mixturewas filtered to give 6.46 g. (73%) of1,2,3,4,4aa,4bB,5.6,7,8,8aa,9,10,10aB-tetradecahydrophenanthrene-2,7-dione bisamidinohydrazone, m.p. 350C.

EXAMPLE 21 3,4,4aa.4b,8.5,6.7.8.8aa.9,lO.lOaB-Dodecahydro-7.7ethylenedimercapto-2(lH)-phenanthrone [111; R and R" are H, X is H Z is(ethylenedithio)C] A solution of 2.83 g. (9.4 mmoles) of 3.4,4aa.4bB,5,-6,-7,8,8aa,9,10,l0aB-dodecahydro-7B-hydroxy- 2(1H)-phenanthrone2.2-ethylene dithioketal (Example 17) in 40 ml. of pyridine was added to40 ml. of pyridine containing 3 g. of chromium trioxide. After 5 days atroom temperature the reaction mixture was added to 500 ml. of ethylacetate. The mixture was filtered and the filtrate was concentrated to aresidue by warming in vacuo. Ether (200 ml.) was added to the residueand more unwanted solid was separated. The ether was concentrated and 2g. of 3,4,4aa,4b,6,5,6,7.8,8aa,9,10-,10aB-dodecahydro-7,7-ethylenedimercapto-2(1H)- phenanthrone, m.p.13l-132C. was obtained from the mother liquor (yield 76%).

EXAMPLE 22 Lithium-ammonia reduction of 2.04 g. of 4,4aa,4b,5-,6,7,8,8aa,9,10-decahydro-7B-hydroxy-4b/3-methyl- 2(3H)-phenanthroneaccording to the procedure described above in Example 13 afforded 0.99g. of 3,4,4aa.4b, 5,6,7,8,8aa,9,10,lOaB-dodecahydro-7B-hydroxy-4bB-methyl-2( lH)-phenanthrone [III; R is CH R is H, X is H Z is(B-HO)CH], m.p. l0S-107C. and a second crop of 0.1 g., m.p. 103105C.(54%).

1,2,3,4,4aa,4b,5,6,7,8,8aa,9,10,10a};-Tetradecahydro-4bB-methylphenanthrene-2a,7B-diol (0.19 g., m.p.171-175C.) was also isolated (9%). Recrystallization from acetonitrileafforded a sample that melted at l82184C. This compound can be oxidizedto the corresponding 2,7dione.

EXAMPLE 23 1B,4bB-Dimethyl-3,4,4aa, 4b, 5,6.7,8,8aoz,9,l0,10aB-dodecahydro-7B-hydroxy- 2(lH)-phenanthrone [111; Rand R" are CH X is Dry liquid ammonia was prepared by treatment of 300ml. of liquid ammonia with lithium wire until the blue color persisted,followed by distillation until l00 ml. of liquid ammonia had beencondensed in the reaction vessel. To the dry liquid ammonia was addedwith stirring 0.16 g. (23 mmoles) oflithium wire followed by dropwiseaddition of a solution of 1.00 g. (4.29 mmoles) of4,4aa,4b,5,6,7,8,8aa,9,l0-decahydro-7B-hydroxy-5bB-methyl-2(3H)-phenanthrone in 15 ml. of tetrahydrofuran and35 ml. of anhydrous ether over a 10 minute period. The mixture wasstirred for 30 minutes and then treated with 1.2 ml. of methyl iodidewhich immediately discharged the blue color. The ammonia was allowed toevaporate and the residue was treated with ml. of water and extractedwith 250 ml. of ether. The extract was washed with water and saturatedsalt solution and dried (MgSO The residue (1.05 g.). obtained uponevaporation of the solvent, was chromatographed on 30 g. of silica gel.Elution with 1:1:3 methylene dichloride-etherpentane affordedcrystalline material which, upon recrystallization from acetonitrile,furnished 0.34 g. of product, m.p.

' 1 l5120C. Recrystallization of the latter from acetonitrile gave1B,4bfl-dimethyl- 3 ,4,4aa,4b,5,6,7,8,8az,9, l O, l OaB-dodecahydro-7B-hydroxy-2( ll-l )-phenanthrone, m.p. l 29-132C.

EXAMPLE 244,4aa,4bB,5,6,7,8,8aa,9,l0-Decahydro-7a,l0adihydroxy-2(3H)-phenanthrone[Xllz 7B-OH] and 1,2,3 ,4,4,aa,4b,5,6,7 ,9, l 0, lOaB-dodecahydro-7-oxophenanthrene-2a,4bB-diol [Xlll; Za-OH] Themicroorganism, Cunninghamella bainieri (American Type Culture CollectionNo. 9244) was grown in surface growth l days old agar slants at 26C.containing as a nutrient medium:

(A) Maltose 40 gr. Proteose peptone l0 gr. Agar l5 gr. Disitlled waterto 1 liter,

and suspended in distilled water. Five ml. portions of the suspensionwere used to inoculate 500 ml. Erlenmeyer flasks each containing 100 ml.of a sterilized medium (autoclaved at lbs. per sq. in. for minutes)containing:

(B) Cerelose (glucose) 5% Edamine (An enzymatic hydrolysate 2% of milkprotein (Sheffield Farms Co.) Cornsteep 0.5% Tap water to 1 liter Theseeded Erlenmeyer flasks were grown for 72 hours at 26C. on a shakerrotating at 2l0 cycles per minute. Fourteen-liter jar fermentors wereprepared, each containing 10 liters of sterile medium B (sterilized for45 minutes at 15 lbs. pressure) described above, and seeded with 10%quantitiesof inocula. The inoculated fermentors were agitated at 400r.p.m. and aerated with an air supply of 4 liters of air per minute at atemperature of 27C. for 48 hours. After this period of time, a solutionof 3 gr. of 4,4aa,4bl3,5,6,7,8,8aa,9,l0- decahydro-7B-hydroxy-2( 3H)-phenanthrone (Example 9) dissolved in 15 ml. of N,N-dimethylformamidewas added to each tank. Antifoam was added as needed during thefermentation cycle.

Samples were taken from the tanks every 24 hours and analyzedchromatographically. Further incubation for 144 hours after addition ofthe substrate indicated that this material had disappeared and theformation of extract more polar metabolites was observed. Thefermentation was terminated and the whole fermentation mash adjusted topH 4.0 with 50% hydrochloric acid and extracted twice with l0-literportions of methylene dichloride. The extracts were combined andconcentrated under reduced pressure to a residue. This residue wastriturated twice with 250-ml. portions of npentane to remove some oils.The pentane washed fermentation dextract (43 g.) from 21 g. of substratewas dissolved in ethyl acetate and put on 2 kg. of silica gel. Thecolumn was eluted with ethyl acetate. The first 8 liters eluted brownoils which were discarded. The next 7.5 liters of ethyl acetate eluted4.38 g. of a mixture of hydroxylated products. Continued elution withethyl acetate afforded 5.98 g. of oil containing mostly the more polar4,4a,4bB,5,6,7,8,8aB,9,IO-decahydro-7B,l0a-dihydroxy-2(3H)-phenanthrone. After preparative thick layerchromatography of these two fractions 1.45 g. of 4,4aa,4bfl,5,6,7,8,8aa,9,lO-decahydro- 7B,10a-dihydroxy-2(3H)-phenanthrone wasobtained, m.p. l43-146C. Recrystallization from acetone containing ethergave a sample with m.p. l55l56C.

From the less polar band I g. of l,2.3.4.4aa,4bB.5,6,- 7 ,9, l 0, l0aB-dodecahydro-7-oxophenanthrone- 2a,4bB-diol, m.p. l5l-l54C. wasobtained. This material was recrystallized from acetone containing etherto give a sample with m.p. l63-l65C. indistinguishable by infraredanalysis, TLC analysis and mixed melting point from a sample prepared byan alternative chemical method as described below.

By substituting as the substrate in the foregoing preparation,4,4aa,4b,5,6,7.8,8aa,9.10-decahydro-7B- hydroxy-4bB-methyl-2( l H)-phenanthrone (XI), there can be obtained4,4aa,4b,5,6,7.8,8aa,9,IO-decahydro-4bB-methyl-7B,lOa-dihydroxy-2(3H)-phenanthrone.

In the foregoing fermentation process, the organism Cunninghamellabainieri can be replaced by Cunninghamella verticillator orCunninghamella elegans.

EXAMPLE 25 a. l ,2,3,4,4aa.5,6,7,8,9,10, lOaB-Dodecahydro-7-oxo-2aphenanthrol.

A solution of 13.8 g. (0.06 mole) of l,2,3,4,4aa,9,l0-,l0aa-octahydro-7-methoxy-2B-phenanthrol and -2aphenanthrol in 50 ml. oftetrahydrofuran was added to 300 ml. of liquid ammonia. Lithium wire(4.7 g., 0.66

mole) was added over a half-hour period with stirring.

After stirring the mixture for a half-hour longer, a mixture of ml. ofabsolute ethanol and 70 ml. of ether (anhydrous) was added to dischargethe blue color. The solution was evaporated to half the volume. Etherand water were added and. after shaking, the layers were separated. Theether was washed with saturated sodium chloride solution and the aqueouslayers were washed with a fresh portion of ether. The combined etherlayers were dried (Na,SO and the ether was removed by warming in vacuo.The remaining residue was taken up in 100 ml. of tetrahydrofuran and 200ml. of methanol. Oxalic acid (10 g.) in ml. of water was added. Thesolution was kept at room temperature for 75 minutes and then added to alarge volume of ether. The layers were separated and the ether layer waswashed several times with saturated sodium bicarbonate solution. Theaqueous layers were washed with a fresh portion of ether. The combinedether layers were dried (Na SO and the solvent was removed by warming invacuo. The residue crystallized from ether containing hexane andafforded 7.9 g. of l,2.3.4,4aa,5,6,7-,8,9,l0,l0aB-dodecahydro-7-oxo-2a-phenanthrol, m.p. l20-l23C.

b. l,2,3,4,4aa,4b,5,6,7,9,l0, l0aB-Dodecahydro-7-oxophenanthrene-2oz,4bB-diol [Xlll; Za-OH] and-2a,4boz-diol fate. The solvent was removed by warming in vacuo, leaving6.3 g. of an oily residue that would not crystallize. The residue waschromatographed on 500 g. of silica gel. Ethyl acetate with 05% methanolwas used for elution. A less polar fraction (2.53 g.) was obtained whichon crystallization and recrystallization from acetone containing hexane,afforded 1.43 g. ofl,2,3,4,4aa,4b,5,6,7,9.lO,10aB-dodecahydro-7-oxophenanthrene-2a,4bB-diol,m.p. l60161C.

A more polar fraction 1.74 g.) afforded, on crystallization andrecrystallization from acetone-hexane. 0.88 g. of1,2.3,4,4aa,4b,5,6,7,9,l0,10aB-dodecahydro-7-oxophenanthrene-2a,4ba-dio1, m.p. l76l77C.

EXAMPLE 26 l,2.3,4,4aa,4b[3,5.6.7,8,8aa,9,10,10aB-Tetradecahydro7B-acetoxyphenanthrene-2,lO-dione [111; R and R are H, Xis 0, Z is (B-CH COO)CH].

A solution of 900 mg. of 4,4aa,4bB,5,6,7,8,8aa,9.ldecahydro-7B,lOa-dihydroxy-2(3H)-phenanthrone (Example 24) in 50 ml. ofacetic acid and ml. of 10% sulfuric acid was kept at room temperature ina nitrogen atmosphere for 24 hours. At the end of this time the solutionwas poured into ice and solid sodium bicarbonate was added. Ether wasadded and the layers were separated. The ether was washed with saturatedsodium bicarbonate solution and then with saturated sodium chloridesolution. The aqueous layers were washed with more ether. The ether wascombined and dried over sodium sulfate. The ether was evaporated bywarming in vacuo leaving a residue that partially crystallized. Ethercontaining hexane was added and 310 mg. of 1,2,3,4,4aa,4bB,5,6,7,8,8aa,9,10,10aB-tetradecahydro-7B-acetoxyphenanthrene-2,lO-dione. Recrystallization fromether gave a sample with m.p. 146-148C.

EXAMPLE 27 l,2.3,4,4aa,4b,5.6.7.9.l0,10aB-Dodecahydro-4bB-hydroxyphenanthrene- 2.7-dione H"; R isOH, R" is H, X is H 2 is O=C, M]

A solution of 1,2,3,4,4aa,4b,5,6,7,9,10,10aB-dodeca-hydro-7-oxophenanthrene-2a,4b[3- diol( Example 24) in 35 ml. ofpyridine was added to 35 ml. of pyridine containing 3 g. of chromiumtrioxide. After standing at room temperature overnight, the reovernightat room temperature. The mixture was added to 150 ml. of concentratedhydrochloric acid and 350 ml. of ice-water and the mixture was extractedwith action mixture was diluted with a large volume of ethyl EXAMPLE 28a. 3,4,4aa,4b,5 .6,7,8 ,8aa,9,10,10aB-Dodecahydro-7B-hydroxy-4bB-methyl-2( l H)-phenanthrone 7-p-t0luenesulfonate.

A solution of 10.0 g. (0.043 mole) of 3,4,4aa,4b,5,6,- 7,8,8aa,9,10,10aB-dodecahydro-7B-hydroxy-4bB- methyl-2( lH)-phenanthrone (Example22) in ml. of pyridine was treated with 9.60 g. (0.050 mole) ofptoluenesulfonyl chloride in 50 ml. of pyridine and kept ether. Theextract was washed with 2N sodium hydroxide solution. dried (MgSO andconcentrated to a residue to give 16.4 g. of3,4,4aa.4b,5.6,7,8,8a0z,9,1O,10a- B-dodecahydr0-7B-hydroxy-4bB-methyl-2(1H phenanthrone 7-p-toluenesulfonate as an amber oil. This oil was usedwithout further purification in the following procedure.

b. Detosylation of 3,4,4aa, 4b,5 ,6,7,8.8aa,9,10,l0aB-dodecahydro7Bhydroxy- 4bB-methyl-2(1H)-phenanthrone7p-toluenesu1fonate A solution of 16.3 g. of the above oily tosylate in100 ml. of s-collidine was heated under reflux for 4 hours.

The solution was cooled and poured into 400 ml. of 2N sulfuric acid. Theacid mixture was extracted with ether and the extract was washed with 2Nsulfuric acid, water and brine. It was dried (MgSO and concentrated to aresidue to give 7.0 g. of an oil which was assumed to be a mixture of Aand A-2-phenanthrones. This mixture was hydrogenated in the followingprocedure without purification.

c. Hydrogenation of the mixture of A and A-2-phenanthrones A solution of0.69 g. of the mixture of phenanthrones described in the precedingexample in 25 ml. of undenatured ethanol was treated with 0.10 g. of 10%palladium-on-eharcoal and the mixture was shaken in a hydrogenatmosphere until one molar equivalent was absorbed (5 minutes). Themixture was filtered and the filtrate was concentrated to a residue bywarming under reduced pressure. The residue was dissolved in ether andthe solution was dried (MgSO and concentrated to give 0.56 g. of3,4,4aa,4b,5,6,7,8,8aa,9,10,a- B-dodecahydro-4bB-methyl-2( 1 H)phenanthrone [111; R is CH;;. R" is H, X is H Z is CH as an amber oil.It was purified by column chromatography on 15 g. of silica ,gel withelution by 1:9 ether-pentane.

EXAMPLE 29 a. 8,8-Dimethyl-l ,2,3',4,4aa,4bl3,5,6,7,8,10,10aB-dodecahydro-7-oxo-2a-phenanthrol [XV; R is H, lower-alkyl is CH Asolution of 27.4 g. (0.125 mole) of 4,4aa,4bB,5 ,6,- 7,-8,8aa,9,101ecahydro-7B-hydroxy-2(3H)- phenanthrone (IX) (Example 9) in 600 ml. oft-butanol was treated with 35 g. (0.310 mole) of potassium tbutoxide.The reaction mixture was flushed with nitrogen. Methyl iodide g., 0.500mole) was added over a half-hour period. The solution was stirred atroom temperature for 1 hour and was finally heated under reflux for 10minutes. The reaction mixture was cooled and dilute hydrochloric acidwas added. Ether and water were added and the layers were separated. Theether was washed with dilute sodium hydroxide and then saturated sodiumchloride solution. The ether was dried (Na SO and evaporated to affordan oily residue that crystallized from ether containing hexane.Recrystallization twice from the same solvent gave 11.0. g. of8,8-dimethyl-1,2,3,4,4aa,4bB,5,6,7,8,10,l0aB-dodecahydro-7-oxo-2a-phenanthrol, m.p. 1 l6-1 18C.

' Upon concentration of the mother liquor another crop of 3.2 g., m.p.1l4116C. was obtained. The mother liquor was chromatographcd on 500 g.of silica gel. Elution with methylene dichloride-ether-pentane (2:5:3)afforded another 5.5 g., m.p. ll6-ll7C. (64%). A sample recrystallizedfrom ether containing hexane melted at l2ll22C.

b. 3,4,4aa,4bB,5,6,7,8,l0,laB-Decahydr0-8,8-dimethyl-7-oxo-2(lH)-phenanthrone [XVl; R is H, lower-alkyl is CH A solution ofl6.6 g. (0.067 mole) of the hydroxy ketone of part (a) in 210 ml. ofpyridine was added to 210 ml. of pyridine containing 16.6 g. (0.166mole) of chromium trioxide. The mixture was stirred overnight and wasthen added to about 700 ml. of ethyl acetate. The mixture was filteredthrough infusorial earth and the solvent was removed by warming invacuo. Ether was added to the residue and more inorganic solids werefiltered away. The ether was concentrated to afford l 1.9

g. of 3,4,4aa,4bB,5,6,7,8,lO,l0aB-decahydro-8,8- dimethyl-7-oxo-2( 1H)-phenanthrone, m.p. l30-l33C. A second cropof 1.21 g., m.p.

l28l 30C. was also obtained. The mother liquor was chromatographed on150 g. of silica gel. Elution with methylene dichloride-ether-pentane(2:3:5) afforded another 0.7 g., m.p. l3ll33C. (83%). A samplerecrystallized from ether melted at l33l34C.

Similarly, starting from l,2,3,4,4aa,4b,5,9,10,10aB-decahydro-2a-hydroxy-4bB-methyl-7(6H)- phenanthrone [XIV; R is CH;,],there can be prepared 3 ,4,4aa,4b,5 ,6,7,8 ,l0,10aB-decahydro-4bB,8,8-trimethyl-7-oxo-2( lH)-phenanthrone [XVI: R is CH;,, lower-alkyl isCH;,]. 3,4,4aa,4b,5,6,7,8,10,10aB- Decahydro-4bfi,8,8-trimethyl-7-oxo-2(l H phenanthrone reacts with ethylene glycol in the presence ofp-toluenesulfonic acid to give the 2-monoethylene glycol ketal. Thelatter ketal is reduced with lithium aluminum hydride to give3,4,4aoz,4b,5,6,- 7,8,l0,l0aB-decahydro-4bB,8,8-trimethyl-7B-hydroxy-2(1H)phenanthrone 2-mono-ethylene glycol ketal, which is further reducedcatalytically in the presence of palladium-on-carbon to give3,4,4aa,4b,5,6.7,8,8aa,9,-

I l0,l0aB-dodecahydro-4bB,8,8-trimethyl-7B-hydroxy- 2( lH)-phenanthrone2-mono-ethylene glycol ketal. The ketal is then cleaved by heating itwith acetic acid to give 3,4,4aa,4b,5 ,6,7,8,8aa,9,10,l OaB-dodecahydro-4bB,8,8-trimethyl-7B-hydroxy-2( 1H phenanthrone [XVlll; R'is CH lower -alkyl is CH m.p. ll2-ll7C. when recrystallized fromisopropyl alcohol.

EXAMPLE 30 a. Mixture of 10aand l0B-acetoxy-8 ,8-dimethyl-3,4,4aa,4bfi,5 ,6,- 7,8,10,10aB-decahydro-7-oxo-2( l H )-phenanthrones Asolution of 250 mg. (1.0 millimoles) of 3,4,4aa-4bB,-5,6,7,8,10,l0aB-decahydro-8,8-dimethyl-7-oxo- 2( lH)-phenanthronein 5 ml. of benzene and 1 ml. of glacial acetic acid was treated with0.17 ml. (1.0 millimoles) of t-butyl peracetate (75% in benzene).Cuprous chloride (1 mg.) was added and oxygen was removed from thereaction mixture by flushing it with nitrogen. The solution was heatedunder reflux in an atmosphere of nitrogen for 22 hours. Another 0.17 ml.(1.0 millimoles) of t-butyl peracetate and a trace of cuprous chloridewere added. After the reaction mixture was heated under reflux foranother 7 hours, the above addition procedure was repeated. The reactionmixture was then heated under reflux for 24 hours. The reaction mixturewas added to ice water. Ether was added and the layers were separated.The ether was washed with saturated sodium bicarbonate and saturatedsodium Evaporation solutions and then dried (Na SO Evaportion of thesolvent afforded an oily residue that was redissolved in ether andfiltered. Evaporation of the solvent by warming in vacuo gave l mg. ofan oily residue. This residue was chromatographed on 19 g. of silicagel. Elution with 400 ml. of methylene dichloride-ether-pentane (2:3:5)gave 50 mg. (20%) of starting diketone. Continued elution with another60 ml. of the same solvent mixture afforded 60 mg. (207:) of the mixtureof 1004- and IOB-acetates.

b. Mixture of 10a and l 0B-acetoxy-8.8-dimethyll ,2.3.4,4aa,4bB,-5,6,7,8.lO,lOaB-dodecahydro-Za-phenanthrol A solution of 2.3 g. (9.3millimoles) of 8,8-dimethyll,2,3,4.4aa,4bB.5,6,7,8. l 0, lOaB-dodecahydro-7-oxo- Za-phenanthrol in 50 ml. of benzene and 5 ml. ofacetic acid was treated with 1.7 ml. (10.0 millimoles) of t butylperacetate (75% in benzene). Cuprous chloride (10 mg.) was added and thereaction flask after being flushed with nitrogen was boiled under refluxin a nitrogen atmosphere for 24 hours. Another 2 ml. of t-butylperacetate was added and the reaction mixture was boiled under refluxfor another 24 hours. The reaction mixture was worked up as describedabove in part (a). The oily residue (2.65 g.) was chromatographed on 200g. of silica gel. Elution with methylene dichlorideether-pentane (223:5)afforded 540 mg. (23%) of starting material. Continued elution withmethylene dichloride-ether (1:4) then gave 690 mg. (19%) of the mixtureof acetates.

EXAMPLE 31 8,8-Dimethyl-3,4.4aa,4bB,5.6.7.8,10.]OaB-Decahydro-7,l0-dioxo-2( 1H )-phenanthrone [XVll: R is H. lower-alkyl isCH;,]

a. The mixture of acetates from parts (a) and (b) of Example 30 werecombined and were dissolved in 30 ml. of 5% methanolic potassiumhydroxide containing 5% water. The solution was boiled under reflux in anitrogen atomsphere for 45 minutes. The reaction mixture was added toice and water. Sodium chloride was added followed by ether. The layerswere separated. The ether was washed twice with saturated sodiumchloride solution. The aqueous layers were washed with a fresh portionof ether and the combined ether layers were then dried (Na SO andevaporated by warming in vacuo to afford 390 mg. of an oily residue. Theresidue, containing a mixture of 1001- and 10B-hydroxy-8,8-dimethyl-3,4,4aa,4bl3,5,6,7,8,lO,l0al3-decahydro-7-oxo-2(lH)-phenanthrones and 10aand10/3-hydroxy-8,8-dimethyll,2,3,4,4aa,4bfi,5,6,7,8 l O,lOaB-dodecahydro-Zaphenanthrols was dissolved in 20 ml. of pyridine andthis solution was added to 20 ml. of pyridine and containing 600 mg. ofchromium trioxide. The reaction mixture was kept at room temperature for40 hours and then added to about ml. of ethyl acetate. The mixture wasfiltered and warmed in vacuo to remove the solvent. Ether was added andmore inorganic solids were filtered away. The ether was evaporated. Theresidue was crystallized from ether and afforded mg.

of 8,8-dimethyl-3,4,4aa4bB.5,6,7.8.10.1021,3- decahydro-7,l-dioxo-2( 1H)-phenanthrone, m.p. 147150C. (23%). Recrystallization from ether gave asample melting at 152l53C.

b. A solution of 19 ml. of t-butyl chromate in carbon tetrachloride, 20ml. of carbon tetrachloride, 6 ml. of acetic acid and 2.5 ml. of aceticanhydride were heated at 50C. in a water bath. A slow stream of air wasblown through the solution while it was being stirred. A solution of 1g. (4.1 millimoles) of 3,4,4aa,4bB.5,6,7.8,10.-IOaB-decahydro-S,8-dimethyl-7-oxc-2( 1H)- phenanthrone in 18 ml. ofcarbon tetrachloride was added during a half-hour period. Thetemperature was maintained at 5070C. for a 2 hour period. This solutionwas stirred at room temperature with a slow stream of air passingthrough for another 16 hours. Carbon tet rachloride (50 ml.) was addedto the reaction mixture (to maintain volume). Oxalic acid (7.5 g., 83millimoles) in 75 ml. of water was added during a half-hour period whilethe solution was being stirred in an ice bath. Oxalic acid (5.25 g. wasagain added and the reaction mixture was stirred for another 2 hours.More carbon tetrachloride and water were added and the layers wereseparted. The aqueous layer was washed with a fresh portion of carbontetrachloride. The carbon tetrachloride solutions were combined and werewashed twice with saturated sodium bicarbonate and once with.

saturated sodium chloride solution. The organic solution was dried (Na-S0 and the solvent was removed by warming in vacuo to afford 320 mg. ofa residue.

The aqueous layers were extracted with ethyl acetate.

and gave another 570 mg. of oily residue upon evaporation.Crystallization from ether afforded 225 mg. of 8,-8-dimethyl-3,4,4aa,4bB-5,6,7,8,10,10aB-decahydro- 7,10dioxo-2(lH)-phenanthrone, m.p. 148-151C.

EXAMPLE 32 Ethyl 3,4.4aa.4bfi.5,6,7.8,8aa,9,10,10aB-dodecahydro-7B-hydroxy-A -phenanthreneacetate (mixture of isomers) [1: R is C 11 R", R'and R are H. X is H Z is (,B-HO)CH] A solution of sodium ethoxide[prepared from 1.6 g. (0.070 mole) of sodium and absolute ethanol] in120 ml. of dry dimethylformamide (DMF) was cooled in an ice bath andtreated dropwise with a solution of 15.5 g. (0.070 mole) of triethylphosphonoacetate in 20 ml. of dry DMF with stirring. The resultingsolution was stirred cold (0C.) for 5 minutes and then a solution of7.68 g. (0.0346 mole) of 7B-hydroxy-3,4,4aa,4bB,5,-6,7,8,8aa,9,10,10aB-d0decahydro-2(1H)- phenanthrone (Example 13) in 30ml. of dry DMF was added dropwise with stirring. This mixture was thenstirred cold (0C.) for 15 minutes and at room temperature for 2 hours.lt was added to 1.5 liter of water and the mixture was made acidic with2N hydrochloric acid. The precipitated product was extracted with etherand the extracts were washed with brine and dried over sodium sulfate.Removal of the ether gave an oily residue which partially crystallizedupon addition of about 25 ml. of ethanol. Dilution of this mixture with300 ml.

of water and filtration afforded 10.4 g. of a crystalline product, m.p.89101C., which was shown by gasliquid phase chromatogrphy (glpc) to be a1:1 mixture of cis and trans isomers together with 1.6% of an impurity.This mixture was purified on silica chromatoplates developed with pureether and then recrystallized from ether-hexane to give ethyl3,4.4aa,4bB,5.6,7.8.8aa.9,- l0,lOaB-dodcahydro-7fi-hydroxy-Aphenanthreneacetate, m.p. 102110C.

EXAMPLE 33 Methyl 1B,4b[3-dimethyl-3.4,4aa,4b.5.6.7.8,8aa,9,10,10aB-dodeca-hydro-7Bhydroxy-A phenanthreneacetate [1; R is CH R is H. R andR" are CH X is H Z is (B-HO)CH] To a suspension of 2.82 g. (0.052 mole)of reagent sodium methoxide in 35 ml. of dry 1,2- dimethoxyethane wasadded 9.5 g. (0.52 mole) of trimethyl phosphonoacetate in 35 ml. of dry1.2- dimethoxyethane and the mixture was stirred for 1 hour at roomtemperature. A solution of 6.5 g. (0.026 mole) of1B,4bB-dimethyl-7B-hydroxy-3.4,4aa,4b.5,6,7,8.8aa.9.10.lOaB-dodecahydro- 2(1H)-phenanthrone(Example 23) in ml. of 1,2- dimethoxyethane was added. Silica platesdeveloped with methanol-ether (1:49) showed that the reaction was about50% complete in 1 hour but that it progressed no further even when themixture was refluxed (84C.) for 5 days. After the reflux period, 25 ml.of water and 500 ml. of ether were added and the layers were separated.The organic layer was washed with brine, dried over magnesium sulfateand concentrated to give 9.0 g. of methyl 1B,4bB-dimethyl- 3,4,4aa,4b,5,6,7,8,8aa,-9,10,10aB-dodecahydro-7B- hydroxy-A-phenanthreneacetate as a viscous oil which contained considerableunreacted ketone. This mixture was hydrolyzed directly, giving acarboxylic acid which was easily separable from ketonic impurity.

EXAMPLE 34 a. Ethyl 3 ,4,4aa,4bfi.5 ,6,7.8,8aa.9,10,10al3-dodecahydro-7-oxo-A -phenanthreneacetate (lsomer A) [1: R is C H R, R' and R" are H, Xis H is O =C] A solution of 25.4 g. (0.087 mole) of ethyl 3,4,4aa-4bB-5,6,7,8,8aa,9,10,10aB-dodecahydro-7B-hydroxy- A -phenanthreneacetate(Example 32) in 220 ml. of pyridine was added in 2 minutes with stirringto a mixture of 21.9 g. (0.22 mole) of chromium trioxide and 220 ml. ofpyridine at room temperature and the resulting mixture was stirredovernight. Ethyl acetate 1.5 liter) was added, the mixture was filteredand the filtrate was concentrated to a residue by warming under reducedpressure. This residue was treated with 400 m1. of ether and furtherinsoluble material was removed by filtration. Concentration of the ethersolution and addition of hexane afforded 6.13 g. of ethyl 3,-4,4aa,4bfi,5,6,7,8,8aa,9,10,10aB-dodecahydro-7-oxo- A-phenanthreneacetate (Is'o'mer A), m.p. 96.5C. when recrystallized fromether-hexane.

3,4,4aa,4b,8,5,6.7,8,8aa,9,10,lOaB-Dodecahydro-ioxo-A-phenanthreneacetic acid (lsomer B) [1; R, R, R and R" are H, X is H Zis O=C].

' ethanol. 200 ml. of 2N aqueous sodium hydroxide was added and thesolution was refluxed in a nitrogen atmosphere for 75 minutes. Thereaction mixture was added to ice-water, neutralized with acetic acidand the product was extracted with ether. The ether extracts wereextracted with 2N sodium hydroxide and these extracts acidified with 2Nhydrochloric acid. The precipitated carboxylic acid was collected andrecrystallized from ethyl acetate to give 4.36 g. of3,4,4aa,4bB,5,6,7,8,8aa,9,10,lOaB-dodecahydro-7-oxo-A""-phenanthreneacetic acid (isomer B), m.p. 220-222C. (vac.) whenrecrystallized from ethyl acetate.

c. Methyl 3,4,4aa,4bB,5,6,7,8,8aa,9,10,10aB-dodecahydro-7- oxo-A-phenanthreneacetate (isomer B) [l; R is CH R, R and R" are H, X is H Zis O=C] The mother liquor residues from separation of the isomer B aciddescribed immediately above contained 8.22 g. (0.0313 mole) of a mixtureof isomer A and isomer B unsaturated carboxylic acids. This solid, m.p.l80l95C., was dissolved in 250 ml. of methanol, 0.10 mole ofdiazomethane in ether was added and the solution was allowed to standovernight. The solvent was removed and the crystalline residue wasrecrystallized from ether by the addition of hexane to give 2.87 g. ofmaterial which melted at ll 30C. Two further recrystallizationsfurnished 1.6 g. of methyl 3,4,4aa,4b-B,5,6,7.8,8aa,9,l0,l0aB-dodecahydro-7-oxo-A""" phenanthreneacetate(isomer B), m.p. l39-l4lC.

EXAMPLE 35 Ethyl l,2,3,4,4aa,4b)3,5,6,7,8,8aa.9,10,IOaB-tetradecahydro-7fl-hydroxy-2-phenanthreneacetate (isomer A) [l; R is C,HR, R and R" are H, X is H,, Z is (B-HO)CH, saturated side chain] Asolution of 12.0 g. (0.041 mole) of ethyl 3,4,4aa,4- bB,5 ,6,7,8,8aa,9,l 0, l OaB-dodecahydro-7B-hydroxy- A -phenanthreneacetate (Example 32)in 300 ml. of absolute ethanol was hydrogenated at 3.9 kg./cm and 25C.for 2% hours in the presence of 1.2 g. of 10% palladium-on-carbon. Themixture was filtered and the filtrate was concentrated to a residue bywarming under reduced pressure. The residue was dissolved in ether andprecipitated by addition of a small amount of hexane to give 4.43 g. ofmaterial, m.p. ll0l l l.5C. Concentration of the filtrate gave 1.07 g.of material, m.p. i06-l08C. (41%). Recrystallization from ethercontaining hexane afforded ethyl 1,2- ,3,4,4aa,4bB,5 ,6,7,8,8aa,9 l 0, lOaB-tetradecahydro- 7B-hydroxy-2-phenanthreneacetate (isomer A), m.p.ll0-l l 1C.

The mother liquor residues were greatly enriched in isomer B but TLCshowed no separation of these isomers when using silica plates deveopedwith 100% ether or 3:7 pentane-ether. These residues were hydrolyzed asdescribed below in Example 53.

By the foregoing procedures the following examples of lower-alkyl esters(l; R is lower-alkyl) were prepared. in most instances the esters werenot purified but were hydrolyzed directly to the corresponding freeacids as described below.

EXAMPLE 36 Methyl 3,4,4aa,4b,5,6,7,8,8aa,9,10,10aB-dodecahydro-4bB-methyl-A phenanthreneacetate [l; R is CH;,, R is H, R isCH R" is H, X is H,, Z is CH from 3,4,4aa,4b,5,6,7,8,8a-

(1,9,10, l OaB-dodecahydro-4bB-methyl-2( 1H phenanthrone (Example 28)and trimethyl phosphonoacetate.

EXAMPLE 37 Methyl 3,4,4aa,4b/3,5,6.7,8,8aa.9. l 0,10aB-dodecahydro-7B-hydroxy-A" phenanthreneacetate [i; R is CH R,R' and R areH, X is H Z is (B-HO)CH], from 7B-hydroxy-3.4,4aa,4bfi,5,6.7.8,8aa.9.lOJOaB-dodecahydro- 2(lH)-phenanthrone(Example 13) and trimethyl phosphonoacetate.

EXAMPLE 38 Ethyl 3,4,4aa,4b,8,5,6,7,8.8aa,9.IOJOaB-dodecahydro-7a-hydroxy-A phenanthreneacetate [l; R is C H R, R and R"are H, Z is (a-HO)CH], from 3,4,4aoz,4bB,5.6,7,8.8aa.9,l-0,l0aB-dodecahydro-7a-hydroxy-Z( 1 H phenanthrone (Example 14) andtriethyl phosphonoacetate.

EXAMPLE 39 Methyl 3,4,4aa,4bB,5,6.7,9,10,10aB-decahydro-7- oxo-A-phenanthreneacetate [i; R is C H R", R and R" are H, X is H,. Z is O=C,A from 3,4.4aa,4b- B,5,6,7,9, l 0, l OaB-decahydro-7-oxo-2( 1Hphenanthrone (Example 18) andtrimethyl phosphonoacetate.

EXAMPLE 40 Methyl 3.4,4aa,4bB,5.6,7,8,8aa,9,l0,10aB-dodecahydro-7,7-ethylenedimercapto-A phenanthreneacetate [i; R is CH;,R", R and R" are H, X is H,, Z is ethylenedithio], from3,4.4aa,4bfl,5,6,7,8- ,8aoz,9. l 0, l0afi-dodecahydro-7,7-ethylenedimercapto- 2( lH)-phenanthrone (Example 21and trimethyl phosphonoacetate.

EXAMPLE 4] Methyl 3,4,4aa,4b,5.6,7.8.8aa.9.l0.l0aB-dodecahydro-4bfi-methyl-7B-hydr0xy-A phenanthreneacetate [i; R is CH;,,R is H, R is CH R is H, X is H Z is (B-HO)CH], from 3,4,4aa,4b,5,6-,7,8,8aa,9, l 0, l 0aB-dodecahydro-7B-hydroxy-4b3- methyl-2(lH)-phenanthrone (Example 22) and trimethyl phosphonoacetate.

EXAMPLE 42 Methyl 3,4,4aa.4b.5,6,7.8,8aa,9,10,10aB-dodecahydroibB-methyl-7-oxo-A phenanthreneacetate [i; R is CH;,, R is H,R' is CH R" is H, X is H Z is O=C], by oxidation of methyl 3,4-,4aa,4b,5,6,7,8,8aa.9.l0,IOaB-dodecahydro-4bB- methyl-7 B-hydroxyA--phenanthreneacetate (Example 41).

EXAMPLE 43 phenanthreneacetate (i; R is CH R is H, R is CH R" is H, X isH Z is O C, A and Methyl l-acetoxy-8,8-dimethyl-3,4,4aa,4bB,5,6,7,8,l0,10aB-decahydro-7-oxo- A a -phenanthreneacetate[l; R is CH;,, R, R and R" are H, X is (CH COO)(H), Z is O==C, A803].

Ethyl 3,4,4aa,4bB,5,6,7,8,8aa,9,10,10a/3- dodecahydro-7,B-hydroxy-Aphenanthreneacetate (Example 32) can be caused to react with phenylisocyanate in boiling acetonitriie to give ethyl3,4,4aa,4bB,5,6,7,8,8aa,9,10,10aB-dodecahydro-7B-(N-phenylcarbamoyloxy)-A phenanthreneacetate [i; R is CHR, R and R are H, X is H Z is (B-C H NHCOO)CH].

EXAMPLE 52 3,4,4aa,4bB,5,6,7,8,8aa,9,10,10aB-Dodecahydro-7- oxo-A-phenanthreneacetic acid (isomer A) [i; R, R, R and R are H, X is H Z isO=C] A solution of 6.0 g. (0.021 mole) of ethyl 3,4,4aa,4b-B,5,6,7,8,8aa,9,l0,lOaB-dodecahydroJ-oxo-A""- a phenanthreneacetate(isomer A) (Example 34a) in 200 ml. of 95% ethanol was treatedwith 80ml. (0.16 mole) of 2N aqueous sodium hydroxide and the solution wasrefluxed for 75 minutes under nitrogen. The reaction mixture was cooled,acidified with acetic acid and concentrated under reduced pressure untilthe ethanol was removed. The product was extracted from the resultingmixture with ether and then extracted from the ether with 2N aqueoussodium hydroxide. Acidification of this extract with concentratedhydrochloric acid precipitated the product which was collected andrecrystallized from ethyl acetate to give 4.2 g. of 3,4,4-aa,4bB,5,6,7,8,8aa,9,10,10aB-dodecahydroJ-oxo- A -phenanthreneaceticacid (isomer A), m.p. 224227C. (vac.).

EXAMPLE 53 l,2,3,4,4aa,4bB,5,6,7,8,8aa,9,l0,lOaB-Tetradecahydro-7B-hydroxy-2-phenanthreneacetic acid (isomer A) [i; R, R,R and R" are H, X is H,, Z is (l3-HO)CH, saturated side chain] The esterof Example 35 (4.5 g.) was hydrolyzed according to the procedure ofExample 52 and the product was recrystallized once from ethyl acetate togive 3.95 g. (97%) of l,2,3,4,4aa,4bB,5,6,7,8,8aa,9,10,10-aBtetradecahydro-7B-hydroxy-2-phenanthreneacetic acid (isomer A), m.p.2l42l6C.

l,2,3,4,4aa,4bfi,5,6,7,8,8aa,9,l0, IOaB-Tetradecahydro-7B-hydr0xy-2-phenanthreneacetic acid (isomer B) Themother liquor residues from Example 35 were hydrolyzed according to theprocedure of Example 52. Two recrystallizations of the product fromethyl acetate and one from acetone afforded 3.13 g. of l,2,3,4,4-aa,4bB,5,6,7,8,8aa,9,l0,l0aB-tetradecahydro-7B- hydroxy-Z-henanthreneacetic acid (isomer B), m.p. l64-l66C.

By the foregoing hydrolysis procedure the following examples of acids (Ris H) were prepared from the corresponding lower-alkyl esters:

EXAMPLE 54 3,4,4aa.9,10,l0aB-Hexahydr0-7-methoxy-A phenanthreneaceticacid [ii; R and R are H, R' is CH ]1 m.p. l74l75C'. (fromacetone-hexane).

EXAMPLE 55 3,4,4aa,4b,5,6,7,8,8aa,9, 10,10aB-D0decahydro- 4bB-methyl-A-phenanthreneacetic acid ii; R and R are H, R is CH R is H, X is H Z isCH m.p. l69l79C. (from ethyl acetate).

EXAMPLE 56 3,4,4aa,4bB,5,6,7,8,8aa,9,lO, lOaB-Dodecahydro-7- oxo-A a-phenanthreneacetic acid (isomer B) [l; R, R, R and R" are H, X is H Zis O=C]. m.p. 220-222C. (vac.) (from ethyl acetate).

EXAMPLE 57 3,4,4aa,4bB,5,6,7,8,8aa,9,10,10aB-Dodecahydro- 7a-hydroxy-A-phenanthreneacetic acid H; R, R, R and R are H, X is H Z is (a-HO)CH],m.p. l73l89C. (from ethyl acetate).

EXAMPLE 58 3,4,4aa,4bB,5,6,7,8,8aa,9,10,10aB-Dodecahydro- 7B-hydroxy-A-phenanthreneacetic acid ii; R, R, R and R" are H, X is H Z is(B-HO)CH], m.p. 205207C. (from ethyl acetate).

EXAMPLE 59 3 ,4,4aa,4bl3,5 ,6,7,8,9, l 0, l 0aB-Decahydro-7-oxo- A-phenanthreneacetic acid (i; R, R, R and R are H, X is H Z is O=C, Am.p. l94200C. (from ethyl acetate).

EXAMPLE 60 3,4,4aa,4bB,5,6,7,8,8aa,9,10,10aB-Dodecahydro-7,7-ethylenedimercapto-A a -phenanthreneacetic acid [1; R, R, R and Rare H, X is H Z is ethylenedithio[, m.p. l87-220C. (from acetone).

EXAMPLE 61 3,4,4aa,4b,5,6,7,8,8aa,9,10,10aB-Dodecahydro-4bB-methyl-7-oxo-A -phenanthreneacetic acid H; R and R are H, R is CH Ris H, X is H Z is O=C], isomer A, m.p. l81184C. (from ethyl acetate);and isomer B, m.p. 2l9-22 1C. (from ethyl acetate).

EXAMPLE 62 3,4,4aa,4b,5,6,7,8,8aa,9,10,10aB-D0decahydro-4bB-methyl-7B-hydroxy-A""" -phenanthreneacet c acid [I; R and R are H, Ris CH;,, R is H, X is H Z is (B-HO)CH], isomer A, m.p. 223225C.; andisomer B, m.p. l98200C. (from ether).

EXAMPLE 633,4,4aa,4b,5,6,7,8,8aa,9,10,10aB-Dodecahydrol[9,4bB-dirhethyl-7B-hydroxy-Aphenanthreneacetic acid H; R and R are H, R and R are CH X is H Z is(B-HO)CH].

EXAMPLE 64 EXAMPLE 65 3,4,4aa,4bfi,5,6,7,8,8aa,9,lO,lOaa-Dodecahydro-7B-hydroxy-A -phenanthreneacetic acid [1;R,

EXAM PLE 6 6 .4aa,4b,5,6,7,9, l 0, l aB-Decahydro-4b[3- hydroxy-7-oxo-A-phenanthreneacetic acid [1; R i

and R are H, R is OH, R is H, X is H Z is O=C, A m.p. 208232C. (fromacetone).

EXAMPLE 67 3,4,4aa,4bB,5 ,6,7,8,8aa,9,10,10aB-Dodccahydro- 7/3-hydroxylO-oxo-A -phenanth reneacetic acid [1; R. R", R and R" are H, X is 0, Zis (B-HO)CH], isomer A, m.p. 237238C. (from acetone); and [somer B, m.p.282283C. (vac) (from acetone).

7 EXAMPLE 67A EXAMPLE 67B 3,4,4aa,4b,5,6,7,8,8aa,9,l0,IOaB-Dodecahydro-4bB,8,8-trimethyl-7B-hydroxy-A phenanthreneacetic acid [1; R and R areH, R is CH R" is H, X is H,, Z is (B-HO)CH, 8,8-(CH m.p. l86-l90C. (fromacetone).

According to the procedure of Example 52 the following acids can beprepared by hydrolysis of the corresponding lower-alkyl esters:

3,4,4aa,9,l0,lOaa-Hexahydro-7-methoxy-A a phenanthreneacetic acid [11; Rand R are H, R is CH 3,4,4aa,4b[3,5,6,7,8,8aa,9,10,10aB-Dodecahydro-7-methyl-7-hydroxy-A -phenanthreneacetic acid [1; R, R, R and R" are H, Xis H Z is X Q L 3,4,4aa,4bfi,5,6,7,8,8aa,9,lOJOaB-Dodecahydro-7a-methoxy-A -phenanthreneacetic acid [1; R, R, R and R are H, X is H Zis (a-CH O)CH], 3,4,4aa,4bB,5,6,7,8,8aa,9,10,10aB-D0decahydro-7/3-fluoro-A -phenanthreneacetic acid [1; R, R, R and R" are H, X is H Zis (B-F(CH], 3,4,4aa,4b/3,5,6,7,8,8aa,9,l0,lOaB-Dodecahydro- 7B-chlor0-A-phenanthreneacetic acid [1; R, R, R and R" are H, X is H Z is (B-CUCH],3,4,4aa,4b/3,5,6,7,8,8aa,9.10,10aB-Dodecahydr0- 7B-br0mo-A-phenanthreneacetic acid [1; R, R, R and R are H, X is H Z is (B-Br)CH],3,4,4aa,4b,5,6,7,8,l0,10aB-Decahydro-4bfi,8,8

trimethyl-7-oxo-A -phenanthreneacetic acid [1; R and R are H, R is CH Ris H, X is H Z is O=C, A 3,4,4aa,4bB,5,6,7,8,10,lOaB-Decahydro-7-oxo-l0-hydroxy-A -phenanthreneacetic acid [1; R,

phenanthreneac etic acid [1; R, R-, and R are A -phenanthreneacet'icacid (Example 61) in 15 ml. of acetic acid was treated with 2.0 ml. of.e,thanedithiol followed by 2.0 ml. of boron trifluoride etherate. Noheat was evolved but a crystalline precipitate formed immediately. After5 minutes the mixture was diluted with 15 ml. of water and filtered. Thefilter cake was washed well with water, air-dried and recrystallizedfrom ml. of acetic acid to give 1.56 g. of 7,7- ethylenedimercapto-3,4,4aa,4b,5,6,7,8,8aa,9',l0,10aB-dodecahydro-4bB- methyl-A-phenanthreneacetic acid, m.p. 254259C.

By replacing the ethanedithiol in the foregoing preparation by a molarequivalent amount of ethylene glycol, 1,3-propylene glycol, or1,3-propanedithiol, there can be obtained, respectively,7,7-ethylenedioxy 3 ,4,4a z,4b,5 ,6,7,8 ,8aa,9,l0,10aB-dodecahydro4bfimethyl-A -phenanthreneacetic acid [1 R and R" areH, R is CH R is H, X is H,, Z is (ethylenediox- 7,7-( 1,3-propylenedioxyW 3 ,4,4aa,4b,5 ,6,7,8,8aa,9,l0,10aB-dodecahydro-4bflmethyl-A-phenanthreneacetic acid [1; R andv R are H, R is CH R is H, x is H,, zis (l,3- propylenedioxy)C], or 7,7-(1,3- propylenedimercapto)- A3,4,4aa,4b,5,6,7,8.8aa,9,10,10aB-dodecahydro-4bB- methyl-A-phenanthreneacetic acid [1; R and R are H, R is CH R is H, X is H Z is(1,3- propylenedithio)C].

Similarly, 3,4,4aa,4b,5,6,7,8,8aa,9,l0,10aBdodecahydro-4bB-methyl-7-oxo-A phenanthreneacetic acid was caused toreact'wi th ben- 7,7-dibenzylmercapto- EXAMPLE 6 9.

ml. of'ethe r was treated with 3.08 g. ("1.7 rnrn o les) ofmonoperphthalic acid-in 21 ml. of ether; The so lu'-' 'tion was keptovernight at room temperature, 150 ml. 7 g of tetrahydrofuran was addedand the solution was' left 5 (3.5 mmoles) of 7,7-

for three more days. Ether (500 ml.) was added and the solution waswashed with saturated sodium sulfite solution and brine and then driedover sodium sulfate. The

solution was concentrated to give a crystalline residue which wastriturated with about 20 ml. of chloroform and collected on a filter;1.13 g., m.p. 266-267C. (dec.). A second crop of 0.19 g., m.p.267-270C., was obtained by concentration of the chloroform washings (92%yield). Recrystallization from acetone gave 7,7-(ethylenedisulfonyl)-3,4,4aa,4b[3,5,6,7,8,8aa,9,10,lOaB-dodecahydro- A -phenanthreneaceticacid, m.p. 27027lC.

Similarly, 7,7-dibenzylmercapto-3,4,4aa,4b,5,6,7,8,8aa,9,10,10aB-dodecahydro-4bB- methyl-A-phenanthreneacetic acid was oxidized to 7,7-dibenzylsulfonyl-3,4,4aa,4b,5,6,7,8,8aa,9,10,10afi-dodecahydro-4bfimethyl-A-phenanthreneacetic acid (I; R and R are H, R is CH R" is H, X is H Z is(C H CH SOQ CI, m.p. l52-l54C.

EXAMPLE 70 3,4,4aa,4b,5 ,6,7,8 ,8aa,9, 10,1 0aB-Dodecahydro-4bB-methyl-7B-pyrrolidino-A -phenanthreneacetic acid [1; R and R are H, R isCH R" is H, X is H,, Z

is (CH,),NCH]

A mixture of 3.10 g. (11.2 mmoles) of 3,4,4aa,4b,5,-6,7,8,8aa,9,10,10aB-dodecahydro-4bB-methyl-7-oxo- A -phenanthreneaceticacid (Example 61), 75 ml. of benzene and 8 ml. (96 mmoles) ofpyrrolidine was heated under reflux for 4% hours with a water separatorattached to the system. This solution was concentrated to a residue bywarming under reduced pressure and the residue was treated with 50 ml.of dry benzene and 3.5 ml. (93 mmoles) of formic acid. The mixture washeated under reflux for 30 minutes, cooled and treated with 1.5 ml. offormic acid. Water (60 ml.)

of ether (100 ml.) were added and the layers were separated. The etherlayer was extracted once with 2N hydrochloric acid and discarded.Addition of the acidic extract to the aqueous portion of the reactionmixture caused precipitation of the hydrochloride salt of the product.Concentrated hydrochloric acid (3 ml.) and 10 ml. of brine were addedand the precipitate was coilected. It was washed well with acetonitrileand then ether to give 2.57 g. of 3,4,4aa,4b,5,6,7,8,8aa,9,l0,l0-aB-dodecahydro-4bB-methyl-7B-pyrrolidino-A"' phenanthreneacetic accidwhich was suitable for conversion to a basic ester.

By replacing the pyrrolidine in the foregoing preparation by a molarequivalent amount of diethylamine or piperidine there can be obtained,respectively, 3,4,4aa,4b,5,6,7,8,8aa,9,l0,lOaB-dodecahydro-4bB-methyl-7fi-diethylamino-A -phenanthreneacetic acid [I; R and R are H, R is CHR" is H, X is H Z is [(C H N]CH, or 3,4,4aa,4b,5,6,7,8,8aa,9,10,]OaB-dodecahydro-4bB-methyl7B-piperidino-A phenanthreneacetic acid [1; R andR are H, R is CH R" is H, X is H Z is (CH NCH].

EXAMPLE 7l 8,8-Dimethyl-7,l0-dioxo-3,4,4aa,4bB,5,6,7,8,10,IOaB-decahydro-A phenanthreneacetic acid [1; R,R, R' and R" are H, X is 0, Z is O=C, 8,8-(CH' A can be prepared fromthe corresponding methyl ester (Example 51) by methods which do not openRing A, for example, by heating the methyl ester with anhydrous lithiumiodide in the presence of a suitable solvent such as collidine.

Conventional aqueous alkaline hydrolysis of the methyl ester leads to acompound where Ring A has been opened as follows:

Methyl 8,8-dimethyl-3,4,4aa,4bl3.5,6,7.8,10,10aB- decahydro-7, lo-diodo-A -phenanthreneacetate (isomer A) (Example 51) (8l0 mg., 2.5millimoles) in 20 ml. of ethanol and 8 ml. of 2N sodium hydroxide wasboiled under reflux in a nitrogen atmosphere for 1 hour. The reactionmixture was added to ice-water and was made acidic with dilutehydrochloric acid. Sodium chloride was added to the reaction mixturewhich was then extracted with ether. The ether was dried (Na,. S0 andevaporated to afford 8 l0 mg. of residue. The residue waschromatographed on g. of silica gel. Elution with aceticacid-ether-pentane (3:50:47) afforded 230 mg. of 5a(2-carboxyethyl)-3,4,4aa,5,8,8aB-hexahydro-6-isopropyl-8-oxo- A -naphthaleneacetic acid(Isomer A), m.p. l86l90C. Recrystallization from ether gave a samplethat melted at l94-l95C.

Similarly, methyl 8.8-dimetl1yl- 3 ,4.4aa,4bB,5 ,6,7,8, l 0,- l0aB-decahydro-7. l O-dioxo- A -phenanthreneacetate (isomer B) (Example51) was hydrolyzed to 5a-(2-carboxyethyl)-3,4,4aa,5.8,-8aB-hexahydro-6-isopropyl-8-oxo- A -naphthalenacetic acid(lsomer B), m.p. 2132l5C. (from ether).

5a-( 2-Carboxyethyl )-3.4,4aa,5 ,8,8aB-hexahydro-6- isopropyl-8-oxo-A-naphthaleneacetic acid (Isomers A and B) were found to haveantibacterial activity when tested in vitro against conventional testorganisms such as Smph. aureus and E. typhi.

EXAMPLE 72 Z-Dimethylaminoethyl3,4,4aa,4bB,5,6,7,8,8aa,9,l0,10aB-dodecahydro-7- oxo-A-phenanthreneacetate (lsomer A) [l; R is CH,CH,N(CH R", R and R are H, Xis H,, Z is O=C] A solution of 4.47 g. (0.017 mole) of the 3,4,4aa,-4b/3,5 ,6,7.8,8aa,9, l 0, l 0aB-dodecahydro-7-oxo- A -phenanthreneaceticacid (lsomer A) (Example 52) in 100 ml. of tetrahydrofuran was treatedwith 0.92 g. (0.17 mole) of sodium methoxide and l ml. of water. Thesolvent was then removed by warming under reduced pressure, 20 ml. ofabsolute ethanol was added and evaporated in the same manner and,finally, two 20-ml. portions of dry benzene were added and evaporated.The resulting dry sodium salt was suspended in ml. of dry benzene, 3.46g. (0.044 mole) of pyridine wasadded, the mixture was immersed in an icebath and 40 ml. of oxalyl chloride was added in a fast stream of dropswith stirring. The mixture was removed from the ice bath, stirred for 10minutes and then concentrated as rapidly as possible under reducedpressure using a water bath at 45C. Application of heat was stopped asthe last of the solvent evaporated,

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1,sub-paragraph (A) wherein R is di-lower-alkylamino-lower-alkyl, X is H2and Z is O C.
 3. A compound according to claim 1, sub-paragraph (A)wherein R is di-lower-alkylamino-lower-alkyl, X is H2 and Z is (HO)CH.4. A compound according to claim 1, sub-paragraph (A) wherein R isdi-lower-alkylamino-lower-alkyl, X is H2 and Z is 5.2-Dimethylaminoethyl 7,7-ethylenedisulfonyl-3,4,4a Alpha ,4b Beta,5,6,7,8,8a Alpha ,9,10,10a Beta -dodecahydro- Delta 2(1H),-phenanthreneacetate, according to claim 4 where R isdimethylaminoethyl, R'', R'''' and R* are hydrogen and n is
 2. 6. Acompound selected from the group consisting ofdi-lower-alkylamino-lower-alkyl 3,4,4a Alpha ,4b,5,6,7,8,8a Alpha ,9,10,10a Beta -dodecahydro-4b Beta ,8,8-trimethyl-7 Beta -hydroxy-Delta2(1H), -phenanthreneacetate and di-lower-alkylamino-lower-alkyl 3,4,4aAlpha ,4b,5,6,7,-8,10,10a Beta -decahydro-4b Beta , 8,8-trimethyl-7-oxo-Delta 2(1H), -phenanthreneacetate.
 7. 2-Dimethylaminoethyl 3,4,4a Alpha,4b,5,6,7,8,10,10a Beta -decahydro-4b Beta ,8,8-trimethyl-7-oxo- Delta2(1H), -phenanthreneacetate, according to claim
 6. 8. A mixture of thetwo corresponding geometric isomers chosen from the compounds offormula:
 9. A mixture according to claim 8, in which the geometricisomers thereof are 3-hydroxy-4,4,14-desmethyl-cassenic and -isocassenicacid Beta -dimethyl-aminoethyl ester.
 10. A mixture according to claim8, in which the geometric isomers thereof are3-hydroxy-4,4-desmethyl-14-epicassenic and -isocassenic acid Beta-dimethyl-aminoethyl ester.